Levorphanol prodrugs and processes for making and using them

ABSTRACT

The presently described technology provides compositions of one or more of oxoacids, polyethylene glycols, and vitamin compounds chemically conjugated to levorphanol ((−)-17-methylmorphinan-3-ol) to form novel prodrugs and compositions of levorphanol.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. provisional application No. 62/485,888, filed on Apr. 14, 2017, which is herein incorporated by reference in its entirety. This application is also related to U.S. provisional application No. 62/485,894, filed on Apr. 14, 2017; U.S. provisional application No. 62/485,890, filed on Apr. 14, 2017; and U.S. provisional application No. 62/485,891, filed on Apr. 14, 2017.

BACKGROUND OF THE INVENTION

Opioids are highly effective as analgesics and are commonly prescribed for the treatment of acute and chronic pain. They are also commonly used as antitussives. The opioids, however, also produce euphoria and are highly addictive. As a result, they are often abused with far reaching social and health related consequences.

Because of the inherent potential for abuse, it is desirable that any pharmaceutical composition containing an opioid agonist be made as abuse-resistant or abuse-deterrent as practical. Illicit users often will attempt to circumvent the extended release properties of these dosage forms by injecting or otherwise misusing the product in order to achieve an immediate release of the opioid agonist.

Levorphanol ((−)-17-methylmorphinan-3-ol) is the (−)-isomer and one of two enantiomers of 17-methylmorphinan-3-ol. The other enantiomer is dextrorphan ((+)-17-methylmorphinan-3-ol). A 1:1 mixture of both enantiomers (levorphanol and dextrorphan) is referred to as racemorphan.

It should be appreciated by those skilled in the art that different stereochemistry may impact the pharmacodynamics, pharmacological and/or pharmacokinetic properties, among other properties, of each isomer or racemic mixture utilized. Further, it should also be appreciated that various conjugations of the isomers to various ligands may also impact the pharmacodynamics, pharmacological and/or pharmacokinetic properties, among other properties, of each resultant conjugate, formulation, and/or end product. For example, those skilled in the art can appreciate the pharmacodynamics, pharmacological and/or pharmacokinetic property differences exhibited and/or observed by different enantiomers (levorphanol and dextrorphan) as well as a mixture such as racemorphan. Moreover, those skilled in the art, also appreciate that the conjugation of those various different enantiomers may impact the various properties observed for the resultant levorphanol or dextrorphan conjugate, formulation and/or end product. Furthermore, those skilled in the art can recognize that conjugation to levorphanol, dextrorphan, or a mixture thereof, may create new enantiomers or diastereomers that may affect their resulting pharmacodynamic, pharmacological and/or pharmacokinetic properties.

Levorphanol is a narcotic analgesic, which interacts predominantly with receptors in the central nervous system (CNS). It has a wide range of pharmacological activities including μ-opioid agonism, (μ-opioid receptor (MOR)), δ-opioid receptor agonism (DOR), κ₁ and κ₂-opioid receptor agonism (KOR), and the nociceptin receptor (NOP), as well as an NMDA (N-methyl-D-aspartate) receptor antagonist and a reuptake inhibitor of both serotonin-norepinephrine (SNRI) and norepinephrine. This multimodal pharmacological profile may be effective for the treatment of CNS conditions including, but not limited to, pain, neuropathic pain, cancer pain, opioid-induced hyperalgesia, pain syndromes that are refractory to other analgesic medications, post-therapeutic neuralgia, depression, narcolepsy and hyperalgesia.

The present technology utilizes covalent conjugation of the opioid levorphanol with certain oxoacids, polyethylene glycols (PEG or PEO), and/or vitamin compounds to decrease its potential for causing overdose or abuse by requiring the active levorphanol to be released through enzymatic or metabolic breakdown of the conjugate in vivo. The present technology also provides methods of delivering levorphanol as conjugates that release the levorphanol following oral administration while being resistant to abuse by circuitous routes such as intravenous (“shooting”) injection and intranasal administration (“snorting”). The compounds and conjugates of this disclosure (aka prodrugs) may be administered alone, or combined with other CNS agents, for the treatment of CNS conditions, including, but not limited to, pain, neuropathic pain, cancer pain, opioid-induced hyperalgesia, pain syndromes that are refractory to other analgesic medications, post-therapeutic neuralgia, depression, narcolepsy and hyperalgesia.

BRIEF SUMMARY OF THE INVENTION

The present technology utilizes conjugation of the opioid levorphanol with certain oxoacids, polyethylene glycols (PEG or PEO), and/or vitamin compounds to decrease its potential for causing overdose or abuse by requiring the active levorphanol to be released through enzymatic or metabolic breakdown of the conjugate in vivo. The present technology also provides methods of delivering levorphanol as conjugates that release the levorphanol following oral administration while being resistant to abuse by circuitous routes such as intravenous (“shooting”) injection and intranasal administration (“snorting”).

Advantages of certain embodiments of the levorphanol prodrugs of the present technology include, but are not limited to, reduced drug abuse potential, reduced or eliminated opioid induced constipation (OIC), reduced risk of chemical or physical manipulation resulting in full dosage of levorphanol release, reduced patient to patient variability in plasma concentrations compared to free levorphanol, improved dosage forms through modifications of the physical and chemical properties of the prodrugs.

In some aspects, the present technology provides an immediate release composition of conjugated levorphanol that allows delivery of the levorphanol into the blood system of a human or animal in a therapeutically bioequivalent manner upon oral administration. In at least one aspect, the compositions/formulations of the current technology can lessen common side effects associated with unconjugated levorphanol and similar compounds. The presently described technology, in at least one aspect, provides a slow/sustained/controlled release composition of conjugated levorphanol that allows slow/sustained/controlled delivery of the levorphanol into the blood system of a human or animal within a therapeutic window upon, for example, oral administration.

In one aspect, the present technology provides a composition comprising at least one conjugate of levorphanol, and at least one oxoacid, polyethylene glycol, vitamin compound, or derivatives thereof. In some aspects, the conjugate further comprises a linker, wherein the linker chemically bonds the at least one levorphanol with the at least one oxoacid, polyethylene glycol, vitamin compound, or derivatives thereof.

In another aspect, the present technology provides at least one conjugate of levorphanol, and at least one oxoacid, polyethylene glycol, vitamin compound, derivatives thereof, or combinations thereof. In some aspects, the conjugate further comprises a linker, wherein the linker chemically bonds the at least one levorphanol with the at least one oxoacid, polyethylene glycol, vitamin compound, or derivatives thereof.

In a further aspect, the present technology provides a composition comprising at least one conjugate of levorphanol, wherein the conjugate has the following general Formula I:

-   -   where L is absent, or is

-   -   Y is absent, or [A-X—Z]_(n)     -   where A, X, Z are independently absent or selected from —O—, —S—         or —(CR¹R²)_(k)—     -   R¹, R² are independently selected from H, alkyl, aryl,         alkylaryl, alkoxy, haloalkyl, or haloaryl     -   n and k are independently 1-4     -   G_(m) is absent or selected independently for each repeating         subunit from H, oxoacid, polyethylene glycol having from 2 to 5         ethylene oxide units, or a vitamin compound, and m is 1-4,         except that m is 1 when G is a hydrogen atom;     -   or pharmaceutically acceptable salt thereof.

In another aspect, the present technology provides at least one prodrug or conjugate having the structure of general Formula I.

In another aspect, the present technology provides at least one prodrug composition comprising at least one conjugate of levorphanol, derivatives thereof or combinations thereof and at least one oxoacid, polyethylene glycol, vitamin compound, or derivatives thereof. In some embodiments, the prodrug composition may also comprise combinations of different levorphanol conjugates, and/or one or more active ingredients, additives, adjuvants, or combinations thereof. In other embodiments, the conjugate of levorphanol of the present technology may be combined with one or more levorphanol conjugates described in U.S. application No. 62/485,891, filed on Apr. 14, 2017, and/or one or more dextrorphan conjugates described in U.S. application No. 62/485,894, filed on Apr. 14, 2017.

In another aspect, the present technology provides at least one prodrug composition comprising at least one conjugate, wherein the at least one conjugate can be, for example, 3-Val-levorphanol; 3-(acetyl-Val)-levorphanol; 3-(PhePhePhe)-levorphanol; 3-(ValValPhe)-levorphanol; 3-(AlaAlaVal)-levorphanol; 3-(GlyGlyAla)-levorphanol; 3-hippuryl-levorphanol; 3-(N-acetyl-Tyr)-levorphanol; 3-(N-acetyl-Ile)-levorphanol; 3-(ProProPhe)-levorphanol; 3-(GlyGly)-levorphanol; 3-(ValGly)-levorphanol; 3-(AlaPro)-levorphanol; 3-cinnamoyl-levorphanol; 3-biotinyl-levorphanol; 3-(N,O-diacetyl-Tyr)-levorphanol; 3-(N,O-diacetyl-Tyr)-OCH₂OC(O))-levorphanol; 3-(N-acetyl-Val-OCH₂OC(O))-levorphanol; 3-(cinnamoyl-OCH₂OC(O))-levorphanol; 3-(benzoyl-OCH₂OC(O)-levorphanol; 3-(butanoyl-OCH₂OC(O))-levorphanol; 3-(N,O-acetyl-Lys-OCH₂OC(O))-levorphanol; 3-(acetyl-OCH(CH₃)C(O))-levorphanol; 3-(acetyl-OCH₂C(O))-levorphanol; 3-(acetyl-OCH(phenyl)C(O))-levorphanol; 3-(methoxy-PEG₂-CH₂C(O))-levorphanol; 3-(methoxy-(ethoxy)-CH₂C(O))-levorphanol; 3-(N-succinoyl-Val)-levorphanol; 3-(H₂N-PEG₄-CH₂CH₂C(O))-levorphanol; 3-(N₃-PEG₄-CH₂CH₂C(O))-levorphanol; 3-(H₂N-PEG₅-CH₂CH₂C(O))-levorphanol; 3-(H₂N-PEG6-CH₂CH₂C(O))-levorphanol; 3-(propyl-SC(O))-levorphanol, 3-(ethoxy-C(O))-levorphanol and anionic salts thereof, including hydrochloride/chloride salts.

In yet another aspect, the present technology provides a method for chemically synthesizing any of the levorphanol conjugates of the present technology by performing the appropriate steps to conjugate levorphanol to at least one ligand.

In a further aspect, the present technology provides a method for treating a human or animal patient having a disease, disorder or condition requiring or mediated by binding of an opioid to the opioid receptors and/or binding of an NMDA antagonist to the NMDA receptor of the patient, comprising orally administering to the patient a pharmaceutically effective amount of at least one levorphanol conjugate of the present technology.

In another aspect, the present technology provides a pharmaceutical kit comprising a specified amount of individual doses in a package, each dose comprising a pharmaceutically effective amount of at least one conjugate of levorphanol.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Chemical structures of some hydroxybenzoates for use in the making of the conjugates of the present technology.

FIG. 2. Chemical structures of some aminobenzoic acids for use in the making of the conjugates of the present technology.

FIG. 3. Chemical structures of some heteroaryl carboxylic acids for use in the making of the conjugates of the present technology.

FIG. 4. Chemical structures of some phenylacetates for use in the making of the conjugates of the present technology.

FIG. 5. Chemical structures of some benzylacetates for use in the making of the conjugates of the present technology.

FIG. 6. Chemical structures of some cinnamates for use in the making of the conjugates of the present technology.

FIG. 7. Chemical structures of some dicarboxylic acids for use in the making of the conjugates of the present technology.

FIG. 8. Chemical structures of some tricarboxylic acids for use in the making of the conjugates of the present technology.

FIG. 9. Chemical structures of some standard amino acids for use in the making of the conjugates of the present technology.

FIG. 10. Chemical structures of some non-standard amino acids for use in the making of the conjugates of the present technology.

FIG. 11. Chemical structures of some synthetic amino acids for use in the making of the conjugates of the present technology.

FIG. 12A. Chemical structures of some water soluble vitamins for use in the making of the conjugates of the present technology.

FIG. 12B. Chemical structures of some fat soluble vitamins for use in the making of the conjugates of the present technology.

FIG. 13. Oral PK curves comparing 3-Val-levorphanol conjugate with unconjugated levorphanol in rats.

FIG. 14. Oral PK curves comparing 3-Phe-levorphanol conjugate with unconjugated levorphanol in rats.

FIG. 15. Oral PK curves comparing 3-(PhePhePhe)-levorphanol conjugate with unconjugated levorphanol in rats.

FIG. 16. Oral PK curves comparing 3-(ValValPhe)-levorphanol conjugate with unconjugated levorphanol in rats.

FIG. 17. Oral PK curves comparing 3-(acetyl-Tyr)-levorphanol conjugate with unconjugated levorphanol in rats.

FIG. 18. Oral PK curves comparing 3-(acetyl-Val)-levorphanol conjugate and 3-(acetyl-Val-OCH₂OC(O))-levorphanol conjugate with unconjugated levorphanol in rats.

FIG. 19. Oral PK curves comparing 3-(N,O-diacetyl-Tyr OCH₂OC(O))-levorphanol conjugate with unconjugated levorphanol in rats.

FIG. 20. Oral PK curves comparing 3-(GlyGly)-levorphanol conjugate, 3-(ValGly)-levorphanol conjugate, and 3-(AlaPro)-levorphanol conjugate, with unconjugated levorphanol in rats.

FIG. 21. Oral PK curves comparing 3-(acetyl-OCH₂OC(O))-levorphanol conjugate and 3-cinnamoly-levorphanol conjugate with unconjugated levorphanol in rats.

FIG. 22. Oral PK curves comparing 3-(butanoyl-OCH₂OC(O))-levorphanol conjugate with unconjugated levorphanol in rats.

FIG. 23. Oral PK curves comparing 3-(H₂N-(PEG)6-CH₂CH₂C(O))-levorphanol conjugate with unconjugated levorphanol in rats.

FIG. 24. Intranasal PK curves comparing 3-Val-levorphanol conjugate with unconjugated levorphanol in rats.

FIG. 25. Intranasal PK curves comparing 3-(ValValPhe)-levorphanol conjugate with unconjugated levorphanol in rats.

FIG. 26. Intranasal PK curves comparing 3-(acetyl-Tyr)-levorphanol conjugate with unconjugated levorphanol in rats.

FIG. 27. Intranasal PK curves comparing 3-(acetyl-Ile)-levorphanol conjugate with unconjugated levorphanol in rats.

FIG. 28. Intravenous PK curves comparing 3-Val-levorphanol conjugate with unconjugated levorphanol in rats.

DETAILED DESCRIPTION

The present technology provides compounds of, or compositions comprising oxoacids, polyethylene glycols (PEG or PEO), and/or vitamin compounds chemically conjugated to levorphanol to form novel prodrugs and conjugates of levorphanol. In some embodiments, the chemical bond between these two moieties can be established by reacting the C-3 hydroxyl of levorphanol with the activated carboxylic acid function of an oxoacid or some vitamin compounds. In other embodiments, the hydroxyl group of an alcohol, hydroxyacid, hydroxyamino acid, or some vitamin compounds are conjugated to the C-3 of levorphanol. In further embodiments, a hydroxyacid is used as linker that is connected to the C-3 of levorphanol on one end (by reaction with its hydroxyl group) and to an alcohol, hydroxyacid, hydroxyamino acid, or vitamin compound on the other end (by reaction with its carboxyl group). In yet further embodiments, a dicarboxylic acid is used as a linker that is connected to the C-3 of levorphanol on one end and to an alcohol, hydroxyacid, hydroxyamino acid, or vitamin compound on the other end.

The use of “opioid” is meant to include any drug that activates the opioid receptors found in the brain, spinal cord and gut. There are four broad classes of opioids: naturally occurring opium alkaloids, such as morphine (the prototypical opioid) codeine, and thebaine; endogenous opioid peptides, such as endorphins; semi-synthetics such as heroine, oxycodone and hydrocodone that are produced by modifying natural opium alkaloids (opiates) and have similar chemical structures; and pure synthetics such as fentanyl and methadone that are not produced from opium and may have very different chemical structures than the opium alkaloids. Additional examples of opioids are hydromorphone, oxymorphone, methadone, levorphanol, dihydrocodeine, meperidine, diphenoxylate, sufentanil, alfentanil, propoxyphene, pentazocine, nalbuphine, butorphanol, buprenorphine, meptazinol, dezocine, and pharmaceutically acceptable salts thereof.

The use of the term “levorphanol” herein means (−)-17-methylmorphinan-3-ol, including all salt forms thereof. In some embodiments, the conjugates contain levorphanol in a racemic mixture (racemorphan). In other embodiments, the levorphanol conjugates are not in a racemic mixture. Depending on the chemical structure of the linkers and oxoacids, polyethylene glycol (PEG or PEO), and/or vitamin compounds, as well as the chiral composition of the levorphanol to which they are attached, the resulting prodrug conjugates can be optically active mixtures of isomers, racemic mixtures, single isomers or combinations thereof.

As used herein, “normative patient” as used herein means a patient that, in general, meets or requires standard and/established treatment modalities, treatment guidelines, prescribing guidelines, among others to achieve a variety of pharmaceutical and/or therapeutic outcomes.

As used herein, the term “conjugate” means a compound or substance formed by bonding two or more chemical compounds or substances in such a way that the bonding is reversible in vivo. For example, a conjugate is the resultant compound formed by bonding at least one pharmaceutical or therapeutically active ingredient with at least one ligand, such as at least one oxoacid, or other substance or compound capable of being a ligand, which is then broken down in vivo into the pharmaceutical or therapeutically active ingredient and ligand. One skilled in the art will appreciate that the term “conjugate” is used in a non-limiting manner and includes various forms including salts, polymorphs, among others.

As used herein, the term “prodrug” refers to a substance converted from an inactive or less active form of a drug to an active drug in the body by a chemical or biological reaction. In the present technology, the prodrug is a conjugate of at least one drug, levorphanol, and at least one oxoacid, for example. Thus, the conjugates of the present technology are prodrugs and the prodrugs of the present technology are conjugates.

Prodrugs are often useful because, in some embodiments, they may be easier to administer or process than the parent drug. They may, for instance, be more bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An embodiment of a prodrug would be a levorphanol conjugate that is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically more active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration. The prodrug is designed to alter the metabolism, pharmacokinetics, or the transport characteristics of a drug in certain embodiments, to reduce or lessen side-effects or toxicity, to improve bioavailability and/or water solubility, to improve the flavor of a drug or to alter other characteristics or properties of a drug in other discrete embodiments.

In some embodiments, the present technology provides at least one prodrug composition comprising at least one conjugate. The at least one conjugate may comprise at least one levorphanol and at least one oxoacid, polyethylene glycol, vitamin compound, derivatives thereof, or combinations thereof. In some embodiments, the conjugate further comprises at least one linker. The linker chemically bonds the levorphanol to the oxoacid, polyethylene glycol, or vitamin compound via one or more covalent bonds.

Depending on the linker and the oxoacid, polyethylene glycol, or vitamin compound conjugated to levorphanol or derivative thereof, the at least one prodrug or conjugate formed can be either a neutral (uncharged), a free acid, a free base or a pharmaceutically acceptable anionic salt form or salt mixtures with any ratio between positive and negative components. These anionic salt forms can include, but are not limited to, for example, acetate, l-aspartate, besylate, bicarbonate, carbonate, d-camsylate, l-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, d-lactate, l-lactate, d,l-lactate, d,l-malate, l-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, d-tartrate, l-tartrate, d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, or undecylenate.

Without wishing to be limited to the following theory, it is believed that the prodrugs/conjugates of the present technology undergo enzyme hydrolysis of the ligand/linker-levorphanol bond in vivo, which subsequently leads to a cascade reaction resulting in rapid regeneration of levorphanol and the respective oxoacid, polyethylene glycol, vitamin compound, or metabolites thereof and/or derivatives thereof. The oxoacids, polyethylene glycols, vitamin compounds, or derivatives thereof, of the present technology are non-toxic or have very low toxicity at the given dose levels and are preferably known drugs, natural products, metabolites, or GRAS (Generally Recognized As Safe) compounds (e.g., preservatives, dyes, flavors, etc.) or non-toxic mimetics or derivatives thereof.

General Structures

In some embodiments, the general structure of the conjugates of levorphanol of the present technology can be represented by the following general Formula I:

-   -   where L is absent, or is

-   -   Y is absent, or [A-X—Z]_(n)     -   where A, X, Z are independently absent or selected from —O—, —S—         or —(CR¹R²)_(k)—     -   R¹, R² are independently selected from H, alkyl, aryl,         alkylaryl, alkoxy, haloalkyl, or haloaryl     -   n and k are independently 1-4     -   G_(m) is absent or selected independently for each repeating         subunit from H, oxoacid, polyethylene glycol having from 2 to 5         ethylene oxide units, or a vitamin compound, and m is 1-4,         except that m is 1 when G is a hydrogen atom;     -   or pharmaceutically acceptable salt thereof.

In some embodiments, L and Y are absent, G is at least one oxoacid, and m is 1-3. Representative examples include, but are not limited to 3-Val-levorphanol; 3-(ValValPhe)-levorphanol; 3-(acetyl-Val)-levorphanol; 3-(PhePhePhe)-levorphanol; 3-(AlaAlaVal)-levorphanol; 3-(GlyGlyAla)-levorphanol; 3-hippuryl-levorphanol; 3-(ProProPhe)-levorphanol; 3-(GlyGly)-levorphanol; 3-(ValGly)-levorphanol; 3-(AlaPro)-levorphanol; 3-cinnamoyl-levorphanol; 3-(acetyl-Tyr)-levorphanol; 3-(N,O-diacetyl-Tyr)-levorphanol; and 3-(N-succinoyl-Val)-levorphanol;

In some embodiments, L is present, A and Z are O, X is —(CR¹R²)_(k)—, and G is at least one oxoacid and m is 1-3. Representative examples include, but are not limited to, 3-(N-acetyl-Val-OCH₂OC(O))-levorphanol; 3-(cinnamoyl-OCH₂OC(O))-levorphanol; 3-(benzoyl-OCH₂OC(O)-levorphanol; 3-(butanoyl-OCH2OC(O))-levorphanol; 3-(N,O-acetyl-Lys-OCH₂OC(O))-levorphanol.

In some embodiments, L and Y are absent, and G is a vitamin compound. Representative examples include, but are not limited to, 3-biotinyl-levorphanol.

In some embodiments, L is present, A, X and Z are absent, and G is a vitamin compound. Representative examples include, but are not limited to, 3-(ascorbyl-C(O))-levorphanol.

In some embodiments, L is present, Y is absent, m is 2 and G_(m) can be represented as G¹ and G² where G¹ is a hydroxycarboxylic acid, and G² is a vitamin compound. Representative examples include, but are not limited to 3-(biotinyl-glycoloyl)-levorphanol.

In some embodiments, L is absent, Y is absent, m is 2 and G_(m) can be represented as G¹ and G² where G¹ is a dicarboxylic acid, and G² is a vitamin compound. Representative examples include, but are not limited to 3-(thiaminyl-succinoyl)-levorphanol.

In some embodiments, L is present, A is —CR¹R²—, X is absent, Z is —CR¹R²— or absent, and G is polyethylene glycol. Representative examples include, but are not limited to 3-(N₃-PEG₄-CH₂CH₂C(O))-levorphanol; 3-(H₂N-PEG₅-CH₂CH₂C(O))-levorphanol; and 3-(H₂N-(PEG)₆-CH₂CH₂C(O))-levorphanol.

In some embodiments, L is present, A is oxygen, X and Z are —(CR¹R²)_(k)— and G is a hydrogen atom. Representative examples include, but are not limited to, 3-(ethoxy-C(O))-levorphanol.

In some embodiments, L is present, A is —(CR¹R²)_(k)—, X and Z are absent, and G is acetic acid. Representative examples include, but are not limited to 3-(acetyl-OCH₂C(O))-levorphanol and 3-(acetyl-OCH(phenyl)C(O))-levorphanol.

Oxoacids

Organic oxoacids (i.e., oxyacids, oxo acids, oxy-acids, oxiacids, oxacids) of the present technology are a class of compounds which contain oxygen, at least one other element, and at least one hydrogen bound to oxygen, and which produce a conjugate base by loss of positive hydrogen ion(s) (protons). Organic acids include carboxylic acids. Carboxylic acids are widespread in nature (naturally occurring), but carboxylic acids can also be non-natural (synthetic). Carboxylic acids can be categorized into numerous classes based on their molecular structure or formula, and many of the different classes may overlap.

Without wishing to limit the scope to one classification, the carboxylic acids of the present technology can be grouped into the following categories: aryl carboxylic acids, aliphatic carboxylic acids, dicarboxylic, polycarboxylic acids, and amino acids.

Some embodiments of the present technology provide oxoacids conjugated to levorphanol, where the carboxylic acid group is directly attached to an aryl moiety. Carboxylic acids directly attached to the aryl moiety include benzoates and heteroaryl carboxylic acids. Benzoates are common in nature and include, for example but are not limited to, aminobenzoates (e.g., anthranilic acid analogs such as fenamates), aminohydroxybenzoates and hydroxybenzoates (e.g., salicylic acid analogs).

The general structure of benzoic acid and benzoic acid derivatives of the present technology can be represented by the following Formula II:

In this Formula II, R¹, R², R³ are independently selected from the group consisting of H, hydroxyl, amino, amine, amide, thiol, cyano, nitro, halogen, imine, alkyl, alkoxy, aryl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, carbonyl, thioether, selenoether, silyl, silyloxy, sulfonyl, and phosphonate.

Suitable hydroxyobenzoic acids can be found in FIG. 1 and include, but are not limited to, benzoic acid, salicylic acid, acetylsalicylic acid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids, 4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflunisal, o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylic acid, protocatechuic acid, gentisic acid, piperonylic acid, 3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylic acid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid, 4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid, vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid, 2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid, 2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid (3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid, 2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA), 4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringic acid, 3,4,5-trimethoxybenzoic acid.

Suitable aminobenzoic acids are shown in FIG. 2 and include, but are not limited to, anthranilic acid, 3-aminobenzoic acid, 4,5-dimethylanthranilic acid, N-methylanthranilic acid, N-acetylanthranilic acid, fenamic acids (e.g., tolfenamic acid, mefenamic acid, flufenamic acid), 2,4-diaminobenzoic acid (2,4-DABA), 2-acetylamino-4-aminobenzoic acid, 4-acetylamino-2-aminobenzoic acid, 2,4-diacetylaminobenzoic acid.

Suitable aminohydroxybenzoic acids include, but are not limited to, 4-aminosalicylic acid, 3-hydroxyanthranilic acid, 3-methoxyanthranilic acid.

In some embodiments, the composition includes a benzoate conjugate comprising at least one levorphanol conjugated to at least one benzoic acid or benzoic acid derivative, salt thereof or combination thereof.

In some embodiments, the benzoates include numerous benzoic acid analogs, benzoate derivatives with hydroxyl or amino groups or a combination of both. The hydroxyl and amino functions may be present in their free form or capped with another chemical moiety, preferably but not limited to methyl or acetyl groups. The phenyl ring may have additional substituents, but the total number of substituents can be four or less, three or less, or two or less.

In yet another embodiment, the present technology provides a prodrug or composition comprising at least one conjugate of levorphanol and at least one heteroaryl carboxylic acid, a derivative thereof, or a combination thereof. The heteroaryl carboxylic acid can be selected from Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI where Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI are:

For these Formulas III, IV, V, VI, VII, VIII, IX, X, and XI, R¹, R², R³ are independently selected from the group consisting of H, hydroxyl, amino, amine, amide, thiol, cyano, nitro, halogen, imine, alkyl, alkoxy, aryl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, carbonyl, thioether, selenoether, silyl, silyloxy, sulfonyl, and phosphonate. Some structures of suitable heteroaryl carboxylic acids for use in the present technology are found in FIG. 3.

In some embodiments, the carboxy group of the aryl carboxylic acids can be attached directly to the aromatic ring. The present technology includes both carbon-only aryl groups and aryl groups with heteroatoms (heteroaryl). The aryl or heteroaryl group which is connected directly to the carboxyl function can be a 6-membered ring and contains no or one heteroatom. In some embodiments, the additional substituted or unsubstituted aromatic or aliphatic rings can be fused to this 6-membered aryl or heteroaryl moiety. In some embodiments, the aryl carboxylic acids may have only one free carboxylic acid group and the total number of phenyl substituents on the 6-membered ring should be four or less, for example, 4, 3, 2 or 1.

Phenylacetates

In some embodiments of the present technology, the aryl carboxylic acids of the present technology comprise a carboxylic group that is separated by one carbon from the aryl moiety. These aryl carboxylic acids include branched phenylpropionic acids (i.e., 2-methyl-2-phenylacetates) or other derivatives of phenylacetate (FIG. 4). The general structure of at least one phenylacetate of the present technology is represented by the following general Formula XII:

For this Formula XII, R¹, R², R³, R⁴, R⁵ are independently selected from the group consisting of H, hydroxyl, amino, amine, amide, thiol, cyano, nitro, halogen, imine, alkyl, alkoxy, aryl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, carbonyl, thioether, selenoether, silyl, silyloxy, sulfonyl, and phosphonate.

Phenylacetic acids encompass various subsets of natural products, metabolites and pharmaceuticals. One such pharmaceutically important subset is “profens”, a type of NSAIDs and derivatives of certain phenylpropionic acids (e.g., 2-methyl-2-phenylacetic acid analogs). Some other phenylacetates have central functions in the phenylalanine and tyrosine metabolism.

Some examples of phenylacetates of the present technology include, but are not limited to, phenylacetic acid (hydratropic acid), 2-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid, homoprotocatechuic acid, homogentisic acid, 2,6-dihydroxyphenylacetic acid, homovanillic acid, homoisovanillic acid, homoveratric acid, atropic acid, d,l-tropic acid, diclofenac, d,l-mandelic acid, 3,4-dihydroxy-d,l-mandelic acid, vanillyl-d,l-mandelic acid, isovanillyl-d,l-mandelic acid, ibuprofen, fenoprofen, carprofen, flurbiprofen, ketoprofen, and naproxen. Some structures of suitable phenylacetates for use in the present technology are found in FIG. 4.

Benzylacetates

In additional embodiments, the aryl carboxylic acids of the present technology comprise a carboxylic group that is separated by two carbons from the aryl moiety. These aryl carboxylic acids include benzylacetates (FIG. 5) and substituted derivatives thereof and analogs of cinnamic acid (FIG. 6). Both classes of compounds are abundant in nature in the form of natural products or metabolites (e.g., phenylalanine metabolism). The general structures of some benzylacetates and cinnamates of the present technology are represented by the following general Formulas XIII and XIV:

For these Formulas XIII and XIV, R¹, R², R³, R⁴, R⁵, R⁶ are independently selected from the group consisting of H, hydroxyl, amino, amine, amide, thiol, cyano, nitro, halogen, imine, alkyl, alkoxy, aryl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, carbonyl, thioether, selenoether, silyl, silyloxy, sulfonyl, and phosphonate.

Benzylacetic acids are defined by an ethylene group between the carboxyl function and the phenyl ring. Both the alkyl chain and the aryl moiety can have substituents, preferably hydroxyl groups. Some compounds of this class can be found in the phenylalanine metabolism.

Some examples of benzylacetates of the present technology include, but are not limited to, benzylacetic acid, melilotic acid, 3-hydroxyphenylpropanoic acid, 4-hydroxyphenylpropanoic acid, 2,3-dihydroxyphenylpropanoic acid, d,l-phenyllactic acid, o,m,p-hydroxy-d,l-phenyllactic acid, or phenylpyruvic acid.

Cinnamates

Cinnamic acids (3-phenylacrylic acids) (FIG. 6) are unsaturated analogs of benzylacetic acids. Cinnamates occur in two isomeric forms: cis (Z) and trans (E). The cinnamate isomers of certain embodiments of the present technology are preferably, but not limited to, the trans configuration. Similar to benzylacetates, derivatives of cinnamic acid can be substituted on the alkenyl or aryl moiety of the molecule. Preferred substituents of some embodiments of the present technology are hydroxyl and methoxy groups. Certain cinnamates are thought to play a key role in phenylalanine metabolism.

Some examples of cinnamates of the present technology include, but are not limited to, cinnamic acid, o,m,p-coumaric acid, 2,3-dihydroxycinnamic acid, 2,6-dihydroxycinnamic acid, caffeic acid, ferulic acid, isoferulic acid, 5-hydroxyferulic acid, sinapic acid, or 2-hydroxy-3-phenylpropenoic acid.

Suitable aliphatic carboxylic acids for use in the present technology include, but are not limited to, for example, saturated, monounsaturated, polyunsaturated, acetylenic, substituted (e.g., alkyl, hydroxyl, methoxy, halogenated, etc.), heteroatom containing or ring containing carboxylic acids. Suitable examples of saturated carboxylic acids include, but are not limited to, for example, methanoic, ethanoic, propanoic, butanoic, pentanoic, hexanoic, heptanoic, octanoic, 2-propylpentanoic acid, nonanoic, decanoic, dodecanoic, tetradecanoic, hexadecanoic, heptadecanoic, octadecanoic, or eicosanoic acid. Suitable monounsaturated carboxylic acids for practice of the present technology include, but are not limited to, for example, 4-decenoic, 9-decenoic, 5-lauroleic, 4-dodecenoic, 9-tetradecenoic, 5-tetradecenoic, 4-tetradecenoic, 9-hexadecenoic, 6-hexadecenoic, 6-octadecenoic, or 9-octadecenoic acid.

Suitable polyunsaturated carboxylic acids for use in the present technology include, but are not limited to, for example, sorbic, octadecadienoic, octadecatrienoic, octadecatetraenoic, eicosatrienoic, eicosatetraenoic, eicosapentaenoic, docosapentaenoic, or docosahexaenoic acids. Suitable acetylenic carboxylic acids for use in the present technology include, but are not limited to octadecynoic, octadecenynoic, 6,9-octadecenynoic, heptadecenynoic, tridecatetraenediynoic, tridecadienetriynoic, octadecadienediynoic, heptadecadienediynoic, octadecadienediynoic, octadecenediynoic, or octadecenetriynoic acids.

Suitable substituted carboxylic acids for practice of the present technology include, but are not limited to, for example, methylpropanoic, isovaleric, methylhexadecanoic, 8-methyl-6-nonenoic, methyloctadecanoic, trimethyloctacosanoic, trimethyltetracosenoic, heptamethyltriacontanoic, tetramethylhexadecanoic, tetramethylpentadecanoic, lactic, glyceric, glycolic, threonic, 3-hydroxypropionic, hydroxyoctadecatrienoic, hydroxyoctadecenoic, hydroxytetracosanoic, 2-hydroxybutyric, 3-hydroxybutyric, 4-hydroxybutyric, 4-hydroxypentanoic, hydroxyoctadecadienediynoic, hydroxyoctadecadienoic, 10-hydroxydecanoic, hydroxydecenoic, hydroxyeicosenoic, hydroxyeicosadienoic, hydroxyhexadecanoic, dihydroxytetracosenoic, dihydroxydocosanoic, hydroxydocosanoic, trihydroxyoctadecanoic, trihydroxyhexadecanoic, trihydroxyicosahexaenoic, trihydroxyicosapentaenoic, 2-methoxy-5-hexadecenoic, 2-methoxy hexadecanoic, 7-methoxy-4-tetradecenoic, 9-methoxypentadecanoic, 11-methoxyheptadecanoic, 3-methoxydocosanoic, diacetoxydocosanoic, 2-acetoxydocosanoic, 2-acetoxytetracosanoic, 2-acetoxyhexacosanoic, 9-oxononanoic, oxodecanoic, oxododecenoic, hydroxyoxodecenoic, 10-oxo-8-decenoic, fluorooctadecenoic, fluorodecanoic, fluorotetradecanoic, fluorohexadecanoic, fluorooctadecadienoic, chlorohydroxyhexadecanoic, chlorohydroxyoctadecanoic, dichlorooctadecanoic, 3-bromo-2-nonaenoic, 9,10-dibromooctadecanoic, 9,10,12,13-tetrabromooctadecanoic, 10-nitro-9,12-octadecadienoic, 12-nitro-9,12-octadecadienoic, 9-nitro-9-octadecenoic, 9-oxo-2-decenoic, 9-oxo-13-octadecenoic, oxooctadecatrienoic, 15-oxo-18-tetracosenoic, 17-oxo-20-hexacosenoic, or 19-oxo-22-octacosenoic acids.

Suitable examples of heteroatom containing carboxylic acids include, but are not limited to, for example, 9-(1,3-nonadienoxy)-8-nonenoic, 9-(1,3,6-nonatrienoxy)-8-nonenoic, 12-(1-hexenoxy)-9,11-dodecadienoic, 12-(1,3-hexadienoxy)-9,11-dodecadienoic, 2-dodecylsulfanylacetic, 2-tetradecylsulfanylacetic, 3-tetradecylsulfanylprop-2-enoic, or 3-tetradecylsulfanylpropanoic acid. Suitable examples of ring containing carboxylic acids include, but are not limited to, for example, 10-(2-Hexylcyclopropyl)decanoic, 3-(2-[6-bromo-3,5-nondienylcyclopropyl)propanoic, 9-(2-hexadecylcyclopropylidene)non-5-enoic, 8-(2-octyl-1-cyclopropenyl)octanoic, 7-(2-octyl-1-cyclopropenypeptanoic, 9,10-epoxyoctadecanoic, 9,10-epoxyl2-octadecenoic, 12,13-epoxy-9-octadecenoic, 14,15-epoxy-11-eicosenoic, 11-(2-cyclopenten-1-yl)undecanoic, 13-(2-cyclopenten-1-yl)tridecanoic, 13-(2-cyclopentenyl)-6-tridecenoic, 11-cyclohexylundecanoic, 13-cyclohexyltridecanoic, 7-(3,4-dimethyl-5-pentylfuran-2-yl)heptanoic, 9-(4-methyl-5-pentylfuran-2-yl)nonanoic, 4-[5]-ladderane-butanoic, 6-[5]-ladderane-hexanoic, or 6-[3]-ladderane-hexanoic acid.

In some embodiments, the levorphanol, derivatives thereof or combinations thereof, can be conjugated to one or more dicarboxylic acids or tricarboxylic acids. Dicarboxylic acids are compounds with two carboxyl groups with a general formula of HOOC—R—COOH, where R can be an alkyl, alkenyl, alkynyl or aryl group, or derivatives thereof. Dicarboxylic acids can have straight carbon chains or branched carbon chains. The carbon chain length may be short or long. Polycarboxylic acids are carboxylic acids with three or more carboxyl groups. Suitable examples of dicarboxylic and tricarboxylic acids for the practice of the present technology include, but are not limited to, for example, oxalic, malonic, succinic, glutaric, adipic, pimelic, suberic, azelaic, sebacic, brassylic, thapsic, malic, tartaric, dihydroxymesoxalic, α-hydroxyglutaric, methylmalonic, meglutol, diaminopimelic, carbamoyl aspartic, fumaric, maleic, mesaconic, 3-methylglutaconic, traumatic, phthalic acid, isophthalic, terephthalic, dipicolinic, citric acid, isocitric, carballylic, or trimesic acid. Some structures of suitable dicarboxylic acids for use in the practice of the present technology can be found in FIG. 7, and some structures of suitable tricarboxylic acids for use in the practice of the present technology can be found in FIG. 8.

Amino Acids

Amino acids are one of the most important building blocks of life. They constitute the structural subunit of proteins, peptides, and many secondary metabolites. In addition to the 22 standard (proteinogenic) amino acids that make up the backbone of proteins, there are hundreds of other natural (non-standard) amino acids that have been discovered either in free form or as components in natural products. The amino acids used in some embodiments of the prodrugs of this invention include natural amino acids, synthetic (non-natural, unnatural) amino acids, and their derivatives.

Standard Amino Acids

There are currently 22 known standard or proteinogenic amino acids that make up the monomeric units of proteins and are encoded in the genetic code. The standard amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, threonine, tryptophan, tyrosine and valine. These standard amino acids have the general structure shown in FIG. 9, where R represents the side chain on the α-carbon.

Non-Standard Amino Acids

Non-standard amino acids can be found in proteins created by chemical modifications of standard amino acids already incorporated in the proteins. This group also includes amino acids that are not found in proteins but are still present in living organisms either in their free form or bound to other molecular entities. Non-standard amino acids occur mostly as intermediates in metabolic pathways of standard amino acids and are not encoded by the genetic code. Examples of non-standard amino acids include but are not limited to ornithine, homoarginine, citrulline, homocitrulline, homoserine, theanine, γ-aminobutyric acid, 6-aminohexanoic acid, sarcosine, cartinine, 2-aminoadipic acid, pantothenic acid, taurine, hypotaurine, lanthionine, thiocysteine, cystathionine, homocysteine, β-amino acids such as β-alanine, β-aminoisobutyric acid, β-leucine, β-lysine, β-arginine, β-tyrosine, β-phenylalanine, isoserine, β-glutamic acid, β-tyrosine, β-dopa (3,4-dihydroxy-L-phenylalanine), α,α-disubstituted amino acids such as 2-aminoisobutyric acid, isovaline, di-n-ethylglycine, N-methyl acids such as N-methyl-alanine, L-abrine, hydroxy-amino acids such as 4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine, 4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, cyclic amino acids such as 1-aminocyclopropyl-1-carboxylic acid, azetidine-2-carboxylic acid and pipecolic acid. Some structures of suitable non-standard amino acids that can be used in some embodiments of the prodrugs of this invention are shown in FIG. 10.

Synthetic Amino Acids

Synthetic amino acids do not occur in nature and are prepared synthetically. Examples include but are not limited to allylglycine, cyclohexylglycine, N-(4-hydroxyphenyl)glycine, N-(chloroacetyl)glycline ester, 2-(trifluoromethyl)-phenylalanine, 4-(hydroxymethyl)-phenylalanine, 4-amino-phenylalanine, 2-chlorophenylglycine, 3-guanidino propionic acid, 3,4-dehydro-proline, 2,3-diaminobenzoic acid, 2-amino-3-chlorobenzoic acid, 2-amino-5-fluorobenzoic acid, allo-isoleucine, tert-leucine, 3-phenylserine, isoserine, 3-aminopentanoic acid, 2-amino-octanedioic acid, 4-chloro-β-phenylalanine, β-homoproline, β-homoalanine, 3-amino-3-(3-methoxyphenyl)propionic acid, N-isobutyryl-cysteine, 3-amino-tyrosine, 5-methyl-tryptophan, 2,3-diaminopropionic acid, 5-aminovaleric acid, and 4-(dimethylamino)cinnamic acid. Some structures of suitable synthetic amino acids that can be used in some embodiments of the prodrugs of this invention are shown in FIG. 11.

Polyethylene Glycols

In some embodiments of the present technology, levorphanol, derivatives thereof or combinations thereof, is conjugated to a polyethylene glycol, or derivatives thereof. In some embodiments, the terminal hydroxyl group of the polyethylene glycol can be substituted with an amino, azide, or methoxy group. Some suitable structures of polyethylene glycols include the following:

wherein k is 1-20 for these structures.

Vitamin Compounds

In some embodiments of the present technology, levorphanol, derivatives thereof, or combinations thereof, is conjugated to one or more vitamin compounds. The vitamin compounds include both water soluble and fat soluble vitamins or derivatives thereof. Useful vitamin compounds are those that have one or more carboxylic acid groups, one or more hydroxyl groups, or one or more other reactive functional groups that can form a bond with levorphanol either directly or through one or more linkers. Examples of water soluble vitamins that could be conjugated to levorphanol include biotin, folate (folic acid), niacin, pantothenic acid, riboflavin, thiamin, pyridoxine, and ascorbic acid. Examples of fat soluble vitamins that could be conjugated to levorphanol include Vitamin A (retinol), vitamin D₂ (ergocalciferol), vitamin D₃ (cholecalciferol), vitamin E (tocopherols and tocotrienols, including alpha, beta, gamma, and delta-tocopherol), and vitamin K (phylloquinone). Some structures of suitable water soluble vitamins and fat soluble vitamins for use in the present technology are found in FIGS. 12A and 12B, respectively.

Linkers

In some embodiments of the present technology, the levorphanol, derivatives thereof, or combinations thereof, is conjugated to one or more organic oxoacids, polyethylene glycols, or vitamin compounds via one or more linkers. Linker moieties of the present technology, which connect the one or more organic oxoacids, polyethylene glycols, or vitamin compounds to the levorphanol, derivatives thereof or combinations thereof, can have the following general formulas:

—C(O)O—X—O— or —C(O)X—O—X or —C(O)O—X or C(O)X—O

wherein X for these linker structures is selected from a representative group including alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted alkylaryl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloalkynyl, or substituted cycloalkynyl.

Preferred embodiments of the present technology include linkers where X is at least one aliphatic group. More preferred embodiments include linkers where X is at least one alkyl group.

Physiological Benefits

The above defined prodrugs or conjugates of levorphanol can be given orally and, upon administration, release the active levorphanol after being hydrolyzed, it is believed, in the body. Thus, not to be bound by any particular theory, it is believed that, since the oxoacids, polyethylene glycols, and/or vitamin compounds of this invention are naturally occurring metabolites or mimetics thereof or pharmaceutically active compounds, these prodrugs can be easily recognized by physiological systems resulting in hydrolysis and release of levorphanol. The claimed prodrugs themselves are either not active or have limited pharmacological activity and consequently may follow a metabolic pathway that differs from the parent drug. By choosing suitable oxoacids, polyethylene glycols, and vitamin compounds (“ligands”), the release of levorphanol into the systemic circulation can be controlled even when the prodrug is administered via routes other than oral. In one embodiment, the modified or conjugated levorphanol would release levorphanol similar to free or unmodified or unconjugated levorphanol. In another embodiment, the modified or conjugated levorphanol may have a more rapid release of levorphanol compared to unmodified or unconjugated levorphanol. In another embodiment, the modified or conjugated levorphanol would be released in a controlled or sustained manner. This controlled release can potentially alleviate certain side-effects and improve upon the safety profile of the parent drug. These side-effects may include, dizziness, lightheadedness, drowsiness, nausea, vomiting, constipation, stomach pain, rash, difficulty urinating, difficulty breathing and fainting. In addition, levorphanol and other opioids (opiates) are also highly addictive and prone to substance abuse.

Recreational drug abuse of opioids is a common problem and usually begins with oral doses taken with the purpose of achieving euphoria (“rush”, “high”). Over time the drug abuser often increases the oral dosages to attain more powerful “highs” or to compensate for heightened opioid tolerance. Rapid metabolism and fast duration of action of levorphanol contributes to its likelihood of being abused. This behavior can escalate and result in exploring of other routes of administration such as intranasal (“snorting”) and intravenous (“shooting”). In some embodiments, levorphanol that is conjugated with a suitable ligand does not result in rapid spikes in plasma concentrations after oral administration that is sought by a potential drug abuser. In some embodiments, levorphanol released from the conjugate may have a delayed T_(max) and possibly lower C_(max) than the parent drug. Not to be bound by any particular theory, it is believed that the conjugates of the present technology, when taken orally or by other non-oral routes, reduce, lessen, or do not provide the feeling of a “rush” even when taken orally at higher doses, but still maintain pain relief. In another embodiment, levorphanol conjugated with appropriate ligands of this invention is not hydrolyzed efficiently when administered via non-oral routes. As a result, in some embodiments, the prodrugs of the present technology do not generate as high plasma or blood concentrations of released levorphanol when injected or snorted compared to free levorphanol administered through these routes.

In some embodiments, the conjugates of the present technology, since they comprise ligands covalently bound to levorphanol, are not able to be physically manipulated to release the levorphanol from the conjugated levorphanol by methods, for example, of grinding up or crushing of solid forms.

Opioid induced constipation is a common side effect of pain treatment with opioids. It affects approximately 40-90% of the patients who are chronically taking opioid medication. Additionally, patients suffering from OIC may become resistant to laxative treatments. Although the mechanism is not yet fully understood, it is assumed that the binding of agonists to the peripheral p-opioid receptors in the gastrointestinal (GI) tract is the primary cause of OIC. This opioid receptor activation impairs the coordination of the GI function by the enteric nervous system (ENS) resulting in decreased gut motility by delaying the transit time of fecal content through interference with the normal tone and contractility of the bowels. While the contractions of the circular muscles are increased causing non-propulsive kneading and churning (stasis) and increased fluid absorption, the longitudinal smooth muscle tone is decreased causing reduced forward peristalsis and additional time for desiccating fecal matter. Furthermore, the anal sphincter tone is increased making defecation more difficult. The clinical presentation of these effects typically manifests itself in symptoms of hard/dry stool, straining, incomplete evacuation, bloating and abdominal distention.

In one embodiment, the prodrugs of this invention have no or insignificant activity at the μ-opioid receptors. In another embodiment, they are not subjected to enzymatic hydrolysis until they are absorbed in the gut. Consequently, the active levorphanol is effectively “cloaked” by the attached ligand and may bypass the peripheral p-opioid receptors without affecting the ENS thereby reducing or preventing OIC.

In some embodiments, the at least one prodrug or conjugate of the present technology can be formulated into dosage forms that include but are not limited to tablet, capsule, caplet, troche, lozenge, powder, suspension, syrup, solution, oral thin film (OTF), oral strips, inhalation compounds, suppositories or transdermal patches. In some embodiments, the dosage forms are administered orally. Preferred oral administration forms are solutions, syrups, suspensions, capsules, tablets and OTF. Suitable dosing vehicles of the present technology include, but are not limited to, water, phosphate buffered saline (PBS), Tween in water, and PEG in water.

Solid dosage forms can optionally include at least one or more of the following types of excipients: antiadherents, binders, coatings, disintegrants, gel-forming agents, fillers, flavors and colors, glidants, lubricants, preservatives, sorbents and sweeteners, among others.

Oral formulations of the present technology can also be included in a solution, a suspension or a slurry in an aqueous liquid or a non-aqueous liquid. The formulation can be an emulsion, such as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The oils can be administered by adding the purified and sterilized liquids to a prepared enteral formula, which is then placed in the feeding tube of a patient who is unable to swallow.

Soft gel or soft gelatin capsules may be prepared, for example by dispersing the formulation in an appropriate vehicle (vegetable oils are commonly used) to form a high viscosity mixture. This mixture is then encapsulated with a gelatin based film using technology and machinery known to those in the soft gel industry. The individual units so formed are then dried to constant weight.

Chewable tablets, for example, may be prepared by mixing the formulations with excipients designed to form a relatively soft, flavored, tablet dosage form that is intended to be chewed rather than swallowed. Conventional tablet machinery and procedures, for example, direct compression and granulation, i.e., or slugging, before compression, can be utilized. Those individuals involved in pharmaceutical solid dosage form production are versed in the processes and the machinery used, as the chewable dosage form is a very common dosage form in the pharmaceutical industry.

Film coated tablets, for example may be prepared by coating tablets using techniques such as rotating pan coating methods or air suspension methods to deposit a contiguous film layer on a tablet.

Compressed tablets, for example may be prepared by mixing the formulation with one or more excipients intended to add binding qualities to disintegration qualities. The mixture is either directly compressed, or granulated and then compressed using methods and machinery known to those in the industry. The resultant compressed tablet dosage units are then packaged according to market need, for example, in unit dose, rolls, bulk bottles, blister packs, etc.

The present technology contemplates that the conjugates of the present technology can be formulated into formulations or co-formulations that may further comprise one or more additional components. For example, such formulations can include biologically-acceptable carriers which may be prepared from a wide range of materials. Without being limited to, such materials include diluents, binders and adhesives, lubricants, glidents, gel-forming agents, plasticizers, disintegrants, surfactants, colorants, bulking substances, flavorants, sweeteners and miscellaneous materials such as buffers and adsorbents in order to prepare a particular medicated formulation.

Binders may be selected from a wide range of materials such as hydroxypropylmethylcellulose, ethylcellulose, or other suitable cellulose derivatives, povidone, acrylic and methacrylic acid co-polymers, pharmaceutical glaze, gums, milk derivatives, such as whey, starches, and derivatives, as well as other conventional binders known to persons working in the art. Exemplary non-limiting solvents are water, ethanol, isopropyl alcohol, methylene chloride or mixtures and combinations thereof. Exemplary non-limiting bulking substances include sugar, lactose, gelatin, starch, and silicon dioxide.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations of the present technology can include other suitable agents such as flavoring agents, preservatives and antioxidants. Such antioxidants would be food acceptable and could include vitamin E, carotene, BHT or other antioxidants.

Other compounds which may be included by admixture are, for example, medically inert ingredients, e.g., solid and liquid diluents, such as lactose, dextrose, saccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules and water or vegetable oil for suspensions or emulsions; lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; gelling agents such as colloidal clays; thickening agents such as gum tragacanth or sodium alginate, binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuff; sweeteners; wetting agents such as lecithin, polysorbates or laurylsulfates; and other therapeutically acceptable accessory ingredients, such as humectants, preservatives, buffers and antioxidants, which are known additives for such formulations.

For oral administration, fine powders or granules containing diluting, dispersing and/or surface-active agents may be presented in a draught, in water or a syrup, in capsules or sachets in the dry state, in a non-aqueous suspension wherein suspending agents may be included, or in a suspension in water or a syrup. Where desirable, flavoring, preserving, suspending, thickening or emulsifying agents can be included.

Liquid dispersions for oral administration may be syrups, emulsions or suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol. In particular a syrup for diabetic patients can contain as carriers only products, for example sorbitol, which do not metabolize to glucose or which metabolize only a very small amount to glucose. The suspensions and the emulsions may contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. The ingredients mentioned herein are not intended to be exhaustive, and one of skill in the art will be able to formulate compositions using known or to be known ingredients.

It is contemplated that the levorphanol conjugates of the present technology can be combined with one or more active substances, such as different levorphanol conjugates, unconjugated levorphanol, narcotic and/or non-narcotic active ingredients, depending on intended indication. Examples of active pharmaceuticals that can be combined with the conjugates of the present technology include, but are not limited to, acetaminophen, phenylpropanolamine, ibuprofen, aspirin, toradol, ketorolac, diclofenac, pheniramine, chlorpheniramine, phenylephrine, pseudoephedrine, pyrilamine, dexyalamine, guaifenesin, codeine, oxycodone, oxymorphone, hydrocodone, hydromorphone, methadone, morphine, fentanyl, benzodiazepines, carbamezine, prochlorperazine, piperazines, piperazine derivatives, dextrorphan, dextromethorphan, magnesium salicylate, magnesium sulfate, and endothelin antagonists. The conjugated levorphanol of the present technology can be formulated with one or a combination of these or other active substances or as a standalone active ingredient without any other actives.

The amounts and relative percentages of the different active and inactive components of the formulations of the current technology can be modified, selected and adjusted in order to arrive at desirable formulations, dosages and dosage forms for therapeutic administration of the compounds, products, compositions, conjugates and prodrugs of the current technology.

The compositions comprising the levorphanol conjugates or prodrugs may be used in methods of treating a patient having a disease, disorder, condition, or syndrome requiring or mediated by binding or inhibiting binding of an opioid to the opioid receptors and/or of an NMDA antagonist to the NMDA receptor of the patient. In some embodiments, the conjugate prodrugs or compositions of the present technology may be administered for the relief or treatment of pain, including acute, chronic, nociceptive, neuropathic, central, and/or peripheral pain.

In further embodiments, compositions comprising the levorphanol conjugates of the present technology may be used as anesthetic or for the treatment of such conditions as hyperalgesia, Alzheimer's disease, pseudobulbar affect (PBA), and post-traumatic stress disorder (PTSD). In certain embodiments, the compositions comprising the levorphanol conjugates of the present technology may be used in combination with quinidine for the treatment of PBA and/or PTSD. In other embodiments, compositions of the present technology may potentiate the effects of certain opioids, such as for example oxycodone, in suppressing neuropathic pain, thus potentially permitting a lower dose of oxycodone to be administered to a patient and thereby decreasing side effects of oxycodone treatment of neuropathic pain in said patient.

Not to be bound by any one theory it is believed that the central glutaminergic system is involved in the transmission and modulation of pain signals. Prolonged binding of opioids to opioid receptors leads in part to pathological activation of NMDA receptors, an ionotropic glutamate receptor, and increase in NMDA calcium channels. The activated NMDA receptor facilitates the inward flow of calcium which in turn activates opioid receptor phosphorylation by protein kinase C. This phosphorylation inactivates the opioid receptor resulting in opioid tolerance and in central sensitization accompanied by enhanced nociception. The latter may manifest opioid-induced hyperalgesia (OIH) in the patient.

Through similar mechanisms, sustained and repeated NMDA receptor activation caused by, for example, upregulation of glutamate transporters and the associated reduction in glutamate uptake following nerve damage can lead to neuropathic pain.

Blocking the NMDA receptor by NMDA receptor antagonists such as levorphanol may disrupt the glutaminergic pathways, and thus provide relief for OIH and reduce opioid tolerance. As a result, levorphanol may be suitable for opioid rotation. Switching opioid therapy from, for example, oxycodone or morphine to levorphanol may improve patient analgesia through its unique opioid receptor activity profile as well as through blocking of NMDA receptors. In addition, blockage of the NMDA receptor by levorphanol may treat neuropathic pain by modulating the action of glutamate in the glutaminergic transmission of nociceptive signals.

Treatment comprises orally administering to the patient a pharmaceutically effective amount of at least one conjugate of levorphanol as described in the present technology. The patient may be a human or animal patient. As used herein, the term animal is used in the veterinary sense and does not include humans. Human patients who may be treated include neonatal patients, pediatric patients, adolescent patients, adult patients, geriatric patients, elderly patients, and normative patients. In some embodiments, the conjugate can exhibit a lower, equivalent, or higher AUC when compared to an equivalent molar amount of unconjugated levorphanol, and can exhibit a slower, similar, or faster rate of release. In other embodiments, at least one conjugate can exhibit less variability in the oral PK profile when compared to unconjugated levorphanol.

Dosing of the prodrugs or compositions will be dependent on the age and body weight of the patient, and the severity of the symptoms to be treated. In some embodiments, dosages of the levorphanol conjugate of the present technology include, but are not limited to, formulations including from about 0.1 mg or higher, alternatively 0.5 mg or higher, alternatively from about 2.5 mg or higher, alternatively from about 5.0 mg or higher, alternatively from about 7.5 mg or higher, alternatively from about 10 mg or higher, alternatively from about 20 mg or higher, alternatively from about 30 mg or higher, alternatively from about 40 mg or higher, alternatively from about 50 mg or higher, alternatively from about 60 mg or higher, alternatively from about 70 mg or higher, alternatively from about 80 mg or higher, alternatively from about 90 mg or higher, alternatively from about 100 mg or higher of the levorphanol conjugate, and include any additional increments thereof, for example, 0.1, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.9 or 1.0 mg and multiplied factors thereof, (e.g., ×1, ×2, ×2.5, ×5, ×10, ×100, etc).

In some embodiments, compositions comprising the levorphanol conjugates of the present technology could be orally administered at a dosing regimen of one time a day, alternatively two times a day, alternatively four times a day. In some embodiments, doses of the composition comprising the levorphanol conjugate could be administered at 1 dose every 4 to 6 hours, alternatively 1 to 2 doses every 4 to 6 hours, alternatively 6 to 8 hours, alternatively 6 doses in a 24 hour period.

In some embodiments, compositions comprising the levorphanol conjugates of the present technology could be administered for a period of about 3 days, alternatively about 5 days, alternatively about 7 days, alternatively about 10 days, alternatively about 12 days, alternatively about 14 days, alternatively about 21 days, alternatively about 30 days, alternatively about 60 days, alternatively about 90 days, or alternatively about 120 days, among others. It should also be appreciated by those skilled in the art that, in some embodiments, rotational dosing utilizing one or more compositions of the present technology, or rotational dosing wherein one or more compositions of the present technology are used in conjunction with one or more opioids, such as, for example hydrocodone, hydromorphone, oxycodone, or oxymorphone, or conjugates of one or more opioids, is also envisaged.

Pharmaceutical Kits

In some embodiments, the present technology provides pharmaceutical kits comprising a levorphanol prodrug or composition of the present technology. In some embodiments, a specific amount of individual doses in a package contain a pharmaceutically and/or therapeutically effective amount of the levorphanol prodrug or conjugate of the present technology. In some embodiments, the kit comprises one or more blister packs containing the prodrug or composition of the present technology.

The kit can further include instructions for use of the kit. In some embodiments, the instructions for use are for the treatment of pain in a neonatal, pediatric, adolescent, adult, normative, or geriatric patient. In other embodiments, the instructions for use are for the treatment of any of the diseases, disorders, conditions, or syndromes identified above. The specified amount of individual doses may contain from about 1 to about 100 individual dosages, alternatively from about 1 to about 60 individual dosages, alternatively from about 10 to about 30 individual dosages, including, about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 70, about 80, about 100, and include any additional increments thereof, for example, about 1, about 2, about 5, about 10 and multiplied factors thereof, (e.g., about ×1, about ×2, about ×2.5, about ×5, about ×10, about ×100, etc.).

Synthetic Schemes

The present technology also provides methods for synthesizing the conjugated levorphanol of the present technology. In some embodiments, one or more protecting groups may be attached to any additional reactive functional groups that may interfere with the coupling to levorphanol. Any suitable protecting group may be used depending on the type of functional group and reaction conditions. Some protecting group suitable for use in the present technology include, but are not limited to, acetyl (Ac), tert-butyoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (Moz), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl (PMB), 3,4 dimethoxybenzyl (DMPM), p-methozyphenyl (PMP), tosyl (Ts), or amides (like acetamides, pthalamides, and the like).

In other embodiments, a base may be required at any step in the synthetic scheme of prodrugs of levorphanol of this invention. Suitable bases include, but are not limited to, 4-methylmorpholine (NMM), 4-(dimethylamino)pyridine (DMAP), N,N-diisopropylethylamine, lithium bis(trimethylsilyl)amide, lithium diisopropylamide (LDA), any alkali metal tert.-butoxide (e.g., potassium tert.-butoxide), any alkali metal hydride (e.g., sodium hydride), any alkali metal alkoxide (e.g., sodium methoxide), triethylamine or any other tertiary amine.

Suitable solvents that can be used for any reaction at any step in the synthetic scheme of a prodrug of levorphanol of this invention include, but are not limited to, acetone, acetonitrile, butanol, chloroform, dichloromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, ethanol, ethyl acetate, diethyl ether, heptane, hexane, methanol, methyl tert.-butyl ether (MTBE), isopropanol, isopropyl acetate, diisopropyl ether, tetrahydrofuran, toluene, xylene or water.

In some embodiments, an acid may be used to remove certain protecting groups. Suitable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydriodic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, acetic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid and nitric acid. For certain other protecting groups, a catalytic hydrogenation may be used, e.g., palladium on charcoal in the presence of hydrogen gas.

Provided herein are some reaction schemes that could be used to prepare some embodiments of the levorphanol conjugates of the present technology. It should be understood that the general reaction schemes provided are exemplary, and that one skilled in the art can modify or tailor the reaction schemes to achieve particular outcomes, purposes, and/or advantages.

3-Val-Levorphanol 6:

To a solution of levorphanol (0.12 g, 0.47 mmol), Boc-Val-OH (0.11 g, 0.5 mmol), HOBt (0.066 g, 0.49 mmol) and trimethylamine (0.13 mL, 0.94 mmol) in DMF (6 mL) was added a solution of HBTU (0.186 g, 0.49 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (1 mL) and the solvent was evaporated under reduced pressure. The residue was taken in EtOAc (100 mL), washed with 5% aq. NaHCO₃ (2×60 mL) and brine (1×60 mL). The organic part was dried over anhydrous Na₂SO₄ and evaporated to dryness to give 3-(Boc-Val)-levorphanol 3. The crude product was purified by preparative HPLC.

A solution of 3-(Boc-Val)-levorphanol 3 in 4N HCl in dioxane (6 mL) was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure, the residue was co-evaporated with IPAc and dried to give the compound 6 (0.125 g, 61% from 1) as a white solid.

3-Phe-Levorphanol 7:

A solution of HBTU (0.24 g, 0.63 mmol) in DMF (2 mL) was added to a solution of levorphanol (0.155 g, 0.6 mmol), Boc-Phe-OH (0.11 g, 0.5 mmol), HOBt (0.085 g, 0.63 mmol) and trimethylamine (0.2 mL, 1.5 mmol) in DMF (6 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (1 mL) and the solvent was evaporated under reduced pressure. The residue was taken in EtOAc (120 mL), washed with 5% aq. NaHCO₃ (2×80 mL) and brine (1×80 mL). The organic part was dried over anhydrous Na₂SO₄ and evaporated to dryness to give 3-(Boc-Phe)-levorphanol 4. The crude product was used for next reaction without further purification.

A solution of 3-(Boc-Phe)-levorphanol 4 in 4N HCl in dioxane (10 mL) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, the residue was co-evaporated with IPAc and dried to give the compound 7 (0.26 g, 90% from 1) as a white powder.

3-Ala-Levorphanol 8:

Reaction of 1 and Boc-Ala-OH was performed following the same procedure as described for the synthesis of compound 7 to produce compound 5. Deprotection of 5 with 4N HCl in dioxane gave compound 8 in 92% yield from 1.

3-(AlaAlaVal)-Levorphanol 15:

To a solution of 3-Val-levorphanol 6 (0.075 g, 0.175 mmol) in DMF (6 mL) were added N-methylmorpholine (0.076 mL, 0.7 mmol) and Boc-Ala-Ala-OSu (0.062 g, 0.175 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction was quenched with water (0.5 mL) and the solvent was evaporated under reduced pressure. The residue was partitioned between EtOAc (80 mL) and 5% aqueous NaHCO₃ (60 mL). The EtOAc layer was washed with 5% aq. NaHCO₃ (50 mL), brine (60 mL), dried over anhydrous Na₂SO₄ and evaporated to dryness to give 3-(Boc-AlaAlaVal)-levorphanol 10.

The tripeptide derivative 10 was dissolved in 4N HCl in dioxane (8 mL) and stirred at room temperature for 2 hours. Solvent was evaporated, the residue was co-evaporated with IPAc and dried to give the tripeptide derivative 15 (0.09 g, 90%)

3-(ValValPhe)-Levorphanol 16:

To a solution of 3-Phe-levorphanol 7 (0.13 g, 0.27 mmol) and N-methylmorpholine (0.12 mL, 1.08 mmol) in DMF (6 mL) was added Boc-Val-Val-OSu (0.112 g, 0.27 mmol). The reaction mixture was stirred at room temperature for 3 hours, then at 50° C. for 16 hours. The reaction was quenched with water (0.5 mL) and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC to give 3-(Boc-ValValPhe)-levorphanol 11.

A solution of compound 11 in 4N HCl in dioxane (6 mL) was stirred at room temperature for 2 hours. Solvent was evaporated, the residue was co-evaporated with IPAc and dried to give the tripeptide derivative 16 (0.045 g, 25% from 7) as a white solid.

3-(PhePhePhe)-Levorphanol 17:

To a solution of 3-Phe-levorphanol 7 (0.13 g, 0.27 mmol) in DMF (6 mL) were added N-methylmorpholine (0.12 mL, 1.08 mmol) and Boc-Phe-Phe-OSu (0.138 g, 0.27 mmol). The reaction mixture was stirred at room temperature for 6 hours. The reaction was quenched with water (0.5 mL) and the solvent was evaporated under reduced pressure. The residue was taken in EtOAc (110 mL) and washed with 5% aqueous NaHCO₃ (2×75 mL), brine (70 mL). The organic part was dried over anhydrous Na₂SO₄ and evaporated to dryness to give 3-(Boc-PhePhePhe)-levorphanol 12.

Compound 12 was dissolved in 4N HCl in dioxane (10 mL) and stirred at room temperature for 3 hours. Solvent was evaporated, the residue was co-evaporated with IPAc and dried to give the tripeptide derivative 17 (0.19 g, 90% from 7) as a white solid.

3-(ProProPhe)-Levorphanol 18:

Compound 18 was prepared following the procedure described for the synthesis of compound 16, except Boc-Pro-Pro-OSu in place of Boc-Val-Val-OSu and reaction was performed at room temperature overnight, in 62% yield (from compound 7).

3-(GlyGlyAla)-Levorphanol 19:

A mixture of compound 8 (0.165 g, 0.41 mmol), N-methyl morpholine (0.22 mL, 2 mmol) and Boc-Gly-Gly-OSu (0.135 g, 0.41 mmol) in DMF (8 mL) was stirred at room temperature for 20 hours. Solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC to give the tripeptide derivative 14.

A solution of 14 in 4N HCl in dioxane (8 mL) was stirred at room temperature for 3 hours. Solvent was removed under vacuum, the residue was co-evaporated with IPAc and dried to give 19 (0.85 g, 40% from 8).

3-(N-Succinoyl-Val)-Levorphanol 20:

A solution of compound 6 (0.132 g, 0.31 mmol), triethylamine (0.17 mL, 1.24 mmol) and succinic anhydride (0.046 g, 0.46 mmol) in DMF (8 mL) was heated at 75° C. for 2 hours. Solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC to provide 3-(N-succinoyl-Val)-levorphanol. The purified product treated with 4N HCl in dioxane to give the hydrochloride salt 20 (0.13 g, 85% from 6).

3-Hippuryl-Levorphanol 22:

To a solution of levorphanol 1 (0.103 g, 0.4 mmol), hippuric acid (0.09 g, 0.5 mmol), HOBt (0.06 g, 0.44 mmol) and trimethylamine (0.17 mL, 1.2 mmol) in DMF (6 mL) was added a solution of HBTU (0.166 g, 0.44 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (1 mL) and the solvent was evaporated under reduced pressure. The residue was taken in EtOAc (110 mL), washed with 5% aq. NaHCO₃ (2×70 mL) and brine (1×70 mL). The EtOAc part was dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by preparative HPLC to give 3-hippuryl-levorphanol. The purified product was dissolved in 4N HCl in dioxane (4 mL) and stirred at room temperature for 5 min. The solvent was evaporated under reduced pressure, the residue was co-evaporated with IPAc and dried to obtain hydrochloride salt 22 (0.055 g, 30%)

3-(N-Acetyl-Ile)-Levorphanol 23:

Reaction of levorphanol (0.09 g, 0.35 mmol) with Ac-Ile-OH (0.067 g, 0.38 mmol) was carried out in a manner similar to that described for the synthesis of 22 to obtain 3-(N-acetyl-Ile)-levorphanol. Reaction time was 48 hours. The N-acetyl-isoleucine derivative was purified by preparative HPLC and converted to the corresponding hydrochloride salt by treatment with 4N HCl in dioxane to give the hydrochloride salt 23 (0.019 g, 12%).

3-(N-Acetyl-Tyr)-Levorphanol 25:

Reaction of levorphanol (0.077 g, 0.3 mmol), Ac-Tyr(^(t)Bu)-OH (0.092 g, 0.33 mmol) was carried out following the same procedure as described for the synthesis of 22. Reaction was performed for 48 hours. The crude product was purified by preparative HPLC to get to obtain compound 24 (0.045 g, 29%).

A solution of 24 in 4N HCl in dioxane was stirred at room temperature for 2 hours. Solvent was evaporated under reduced pressure, the residue was co-evaporated with IPAC and dried to give compound 25 in quantitative yield.

3-(Acetyl-OCH(Phenyl)C(O))-Levorphanol 26:

Reaction of levorphanol (0.09 g, 0.35 mmol), O-acetylmandelic acid (0.075 g, 0.38 mmol), was carried out following the same procedure as described for the synthesis of 22. Reaction time was 24 hours. The crude product was purified by preparative HPLC and then converted to HCl salt by treatment with 2N HCl in dioxane to produce hydrochloride salt 26 (0.13 g, 79%)

3-Cinnamoyl-Levorphanol 28:

A solution of cinnamoyl chloride (0.062 g, 0.38 mmol) in CH₂Cl₂ (1 mL) was added to a solution of levorphanol 1 (0.065 g, 0.25 mmol) and trimethylamine (0.1 mL, 0.75 mmol) in CH₂Cl₂ (5 mL) at 0-5° C. After the addition, the reaction mixture was stirred at 5-10° C. for 2 hours. Additional CH₂Cl₂ (80 mL) was added and the organic part was washed with 5% aqueous NaHCO₃ (2×60 mL), brine (1×60 mL). The CH₂Cl₂ part was dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by preparative HPLC to afford 3-cinnamoyl-levorphanol. The purified product was dissolved in 4N HCl in dioxane and stirred for 5 min. at room temperature. Solvent was evaporated under vacuum and the residue was dried to give hydrochloride salt 28 (0.08 g, 64%).

3-(Acetyl-OCH₂C(O))-Levorphanol 29:

A solution of levorphanol 1 (0.103 g, 0.4 mmol) and trimethylamine (0.22 mL, 1.6 mmol) in CH₂Cl₂ (5 mL) was cooled down to 0-5° C. and to this mixture was added a solution of acetyloxyacetyl chloride (0.085 mL, 0.8 mmol) in CH₂Cl₂ (2 mL) drop wise. After the addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (0.5 mL) and the solvent was evaporated under reduced pressure. The product was purified by preparative HPLC and treated with 2N HCl in dioxane to give hydrochloride salt 29 (0.072 g, 45%) as an oil.

3-Acetyl-OCH(CH₃)C(O))-Levorphanol 30:

To a solution O-acetyl lactyl chloride (0.098 mL, 0.78 mmol) in CH₂Cl₂ (2 mL) was added to a solution of levorphanol 1 (0.1 g, 0.39 mmol) and trimethylamine (0.22 mL, 1.56 mmol) in CH₂Cl₂ (6 mL) at 0-5° C. After the addition, the reaction mixture was stirred at 5° C. for 2 hours. Solvent was evaporated under reduced pressure. The residue was dissolved in CH₂Cl₂ (100 mL) and washed with 5% aqueous NaHCO₃ (2×60 mL), brine (1×60 mL). The CH₂Cl₂ part was dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by preparative HPLC and converted to the corresponding hydrochloride salt 30 (0.115 g, 72%) by treatment with 2N HCl in dioxane.

3-(Chloromethyloxycarbonyl)-Levorphanol 32:

A solution of chloromethyl chloroformate 31 (0.052 mL, 0.58 mmol) in CH₂Cl₂ (1 mL) was added to a solution of levorphanol (0.1 g, 0.39 mmol) and trimethylamine (0.16 mL, 1.2 mmol) in CH₂Cl₂ (5 mL) at 0-5° C. After the addition, the reaction mixture was stirred at 0-5° C. for 2 hours. The reaction was quenched with water and solvent was evaporated under reduced pressure. The residue was taken in EtOAc (100 mL), washed with water (1×75 mL), brine (1×70 mL), dried over anhydrous Na₂SO₄ and evaporated to dryness to give 32 as an oil in 95% yield. The crude product was used for the next reaction without further purification.

3-(Benzoyl-OCH₂OC(O)-Levorphanol 34:

A solution of 32 (0.13 g, 0.37 mmol) and sodium benzoate (0.08 g, 0.55 mmol) in DMF (8 mL) was heated at 65° C. for 6 hours. Solvent was evaporated under reduced pressure. The residue was taken in EtOAc (110 mL), washed with 5% aq. NaHCO₃ (2×70 mL) and brine (1×70 mL). The organic part was dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by preparative HPLC to give 34. The purified benzoyl derivative was dissolved in 4N HCl in dioxane, stirrer at room temperature for 5 min. and then solvent was evaporated under vacuum and the residue was dried to give the hydrochloride salt of 34 (0.055 g, 31%)

3-(Butanoyl-OCH₂OC(O))-Levorphanol 35:

Reaction of 32 (0.1 g, 0.28 mmol) sodium butyrate (0.062 g, 0.56 mmol) was carried out in a manner similar to that described for the synthesis of 34 to obtain 35. The crude product was purified by preparative HPLC and was treatment with 4N HCl in dioxane to obtain hydrochloride salt of 35 (0.035 g, 28%).

3-(Cinnamoyl-OCH₂OC(O))-Levorphanol 36:

A solution of 32 (0.14 g, 0.14 mmol) and sodium cinnamate (0.102 g, 0.6 mmol) in DMF (8 mL) was heated at 65° C. for 5 hours. Solvent was evaporated under reduced pressure. The residue was taken in EtOAc (110 mL), washed with 5% aq. NaHCO₃ (2×70 mL) and brine (1×70 mL). The organic part was dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by preparative HPLC and isolated as hydrochloride salt of 36 (0.06 g, 30%) by treatment with 4N HCl in dioxane.

3-(N,O-Acetyl-Lys-OCH₂OC(O))-Levorphanol 37:

A solution of 32 (0.115 g, 0.32 mmol) and Ac-Lys(Ac)-ONa (0.125 g, 0.48 mmol) in DMF (8 mL) was heated at 75° C. for 2 hours. Solvent was evaporated under reduced pressure. The residue was taken in EtOAc (100 mL), washed with 5% aq. NaHCO₃ (2×60 mL) and brine (1×60 mL). The organic part was dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by preparative HPLC and treated with 4N HCl in dioxane to give hydrochloride salt of 37 (0.022 g, 12%).

General Procedure for the Synthesis of Sodium Salt of N-Protected Amino Acids (Boc-AA-ONa):

To a solution or suspension or solution (depending on amino acids) of Boc-AA-OH (2 mmol) in CH₃CN/water (1:1, 3 mL) was added 1N NaOH (standard solution, 1.8 mL) dropwise with stirring. The clear solution was stirred for additional 15 min. and then lyophilized.

3-(Boc-Val-OCH₂OC(O))-Levorphanol 38:

A solution of 32 (0.14 g, 0.4 mmol) and Boc-Val-ONa (0.14 g, 0.6 mmol) in DMF (8 mL) was heated at 60° C. for 6 h. Solvent was evaporated under reduced pressure. The residue was taken in EtOAc (110 mL), washed with 5% aq. NaHCO₃ (2×70 mL) and brine (1×75 mL). The organic part was dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by preparative HPLC to give 38 (0.075 g, 35%).

3-(Val-OCH₂OC(O))-Levorphanol 40:

A solution of 38 in 4N HCl in dioxane (5 mL) was stirred at room temperature for 2 hours. Solvent was evaporated under reduced pressure, the residue was co-evaporated with IPAc and dried to give 40 in quantitative yield. The deprotected derivative 40 was not stable in aqueous solution. Compound 40 was converted to the acetyl derivative 42.

3-(N-Acetyl-Val-OCH₂OC(O))-Levorphanol 42:

A solution of 40 (0.08 g, 0.16 mmol) and TEA (0.13 mL, 0.96 mmol) in CH₂Cl₂ (5 mL) was cooled down to 0-5° C. and a solution of acetyl chloride (0.045 mL, 0.64 mmol) in CH₂Cl₂ (1 mL) was added drop wise. The reaction mixture was stirred at room temperature for 4 hours. Solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc (80 mL) and 5% aqueous NaHCO₃ (60 mL). The EtOAc layer was washed with 5% aq. NaHCO₃ (50 mL), brine (60 mL), dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by preparative HPLC to give 3-(N-acetyl-Val-OCH₂OC(O))-levorphanol.

The purified product was dissolved in 4N HCl in dioxane, stirred for 5 min. and then evaporated to dryness under vacuum and dried to give the hydrochloride salt 42 (0.031 g, 38% from 39)

3-(N,O-Diacetyl-Tyr)-Levorphanol 43:

A solution of 32 (0.14 g, 0.4 mmol) and Boc-Tyr(^(t)Bu)-ONa (0.155 g, 0.44 mmol) in DMF (8 mL) was stirred at room temperature overnight, then at 50° C. for 4 hours. Solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (110 mL), washed with 5% aq. NaHCO₃ (2×70 mL) and brine (1×70 mL). The organic part was dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by preparative HPLC to give 39 (0.085 g, 33%).

Compound 39 was dissolved in 4N HCl in dioxane (5 mL) and the solution was stirred at room temperature for 3 hours. Solvent was evaporated under reduced pressure, the residue was co-evaporated with IPAc and dried to give 41 in quantitative yield (0.074 g, 100%).

A solution of 41 (0.074 g, 0.13 mmol) and TEA (0.15 mL, 1.04 mmol) in CH₂Cl₂ (6 mL) was cooled down to 0-5° C. and a solution of acetyl chloride (0.05 mL, 0.65 mmol) in CH₂Cl₂ (1 mL) was added drop wise at same temperature. After the addition, the reaction mixture was stirred at room temperature for 2 hours. Solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc (90 mL) and 5% aqueous NaHCO₃ (70 mL). The EtOAc layer was washed with 5% aq. NaHCO₃ (50 mL), brine (60 mL), dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by preparative HPLC and then treated with 4N HCl in dioxane to give the hydrochloride salt 43 (0.035 g, 44%).

3-Biotinyl-Levorphanol 45:

A solution of HBTU (0.12 g, 0.32 mmol) in DMF (2 mL) was added to a solution of levorphanol 1 (0.075 g, 0.29 mmol), biotin 44 (0.078 g, 0.32 mmol), HOBt (0.044 g, 0.32 mmol) and trimethylamine (0.12 mL, 0.87 mmol) in DMF (6 mL) at room temperature for 2 days. The reaction was quenched with water (1 mL) and the solvent was evaporated under reduced pressure. 5% Aqueous NaHCO₃ (70 mL) was added to the residue and the mixture was extracted with CH₂Cl₂ (2×60 mL). The combined organic part was washed with 5% aq. NaHCO₃ (60 mL) and brine (1×60 mL), dried over anhydrous Na₂SO₄ and evaporated to dryness to give 3-biotinyl-levorphanol. The crude product was purified by preparative HPLC and treated with 4N HCl in dioxane to give the hydrochloride salt 45 (0.065 g, 41%).

A solution of 2-methoxyethoxy acetyl chloride 46 (0.072 g, 0.46 mmol) in CH₂Cl₂ (1 mL) was added to a solution of levorphanol (0.1 g, 0.39 mmol) and trimethylamine (0.16 mL, 1.2 mmol) in CH₂Cl₂ (5 mL) at 0-5° C. After the addition, the reaction mixture was stirred at 5-10° C. for 2 hours. Additional CH₂Cl₂ (80 mL) was added and the organic part was washed with 5% aqueous NaHCO₃ (2×50 mL), brine (1×60 mL). The CH₂Cl₂ part was dried over anhydrous Na₂SO₄ and evaporated to dryness. The residue was purified by preparative HPLC. The purified product was dissolved in 4N HCl in dioxane (4 mL), stirred at room temperature for 5 min. and then evaporated under reduced pressure to give the hydrochloride salt 48 (0.065 g, 41% from 1).

3-(Methoxy-PEG₂-CH₂C(O))-Levorphanol 49:

To a solution of levorphanol 1 (0.09 g, 0.35 mmol), 2-[2-(2-methoxyethoxy)ethoxy] acetic acid 47 (0.065 mL, 0.42 mmol), HOBt (0.052 g, 0.39 mmol) and trimethylamine (0.15 mL, 1.05 mmol) in DMF (6 mL) was added a solution of HBTU (0.146 g, 0.385 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (1 mL) and the solvent was evaporated under reduced pressure. The residue was partitioned between CH₂Cl₂ (50 mL) and 5% aq. NaHCO₃ (50 mL). The aqueous part was extracted with CH₂Cl₂ (50 mL). The combined organic part was washed with brine (60 mL), dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by preparative HPLC. The purified product was dissolved in 2N HCl in dioxane (4 mL), stirred at room temperature for 5 min. and then evaporated under reduced pressure to give the hydrochloride salt 49 (0.125 g, 78%) as an oil.

To a solution of levorphanol 1 (0.103 g, 0.4 mmol), Boc-NH-(PEG)₄-CH₂CH₂—COOH 50 (0.16 g, 0.44 mmol), HOBt (0.06 g, 0.44 mmol) and trimethylamine (0.17 mL, 1.2 mmol) in DMF (6 mL) was added a solution of HBTU (0.166 g, 0.44 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with water (1 mL) and the solvent was evaporated under reduced pressure. The residue was taken in EtOAc (110 mL), washed with 5% aq. NaHCO₃ (2×60 mL) and brine (1×60 mL). The organic part was dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by preparative HPLC to give 53.

A solution of 53 in 4N HCl in dioxane (6 mL) was stirred at room temperature for 1.5 hours. Solvent was evaporated under pressure, the residue was co-evaporated with IPAc and dried to give the deprotected product 54 as an oil (0.062 g, 27% from 1).

3-(N₃-PEG₄-CH₂CH₂C(O))-Levorphanol 55:

A solution of HBTU (0.146 g, 0.44 mmol) in DMF (2 mL) was added to a solution of levorphanol 1 (0.09 g, 0.35 mmol), N₃-(PEG)₄-CH₂CH₂—COOH 51 (0.112 g, 0.38 mmol), HOBt (0.052 g, 0.38 mmol) and trimethylamine (0.1 mL, 0.7 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 48 hours. The reaction was quenched with water (1 mL) and the solvent was evaporated under reduced pressure. The residue was taken in CH₂Cl₂ (110 mL), washed with 5% aq. NaHCO₃ (1×75 mL) and brine (1×60 mL). The organic part was dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by preparative HPLC. The purified product was dissolved in 2N HCl in dioxane, stirred for 10 min. at room temperature. Solvent was evaporated under pressure, co-evaporated with IPAc and dried to give the hydrochloride salt 55 as on oil (0.076 g, 38% from 1).

3-(H₂N-PEG₆-CH₂CH₂C(O))-Levorphanol 57:

To a solution of levorphanol 1 (0.09 g, 0.35 mmol), Boc-NH-(PEG)₆-CH₂CH₂—COOH (0.175 g, 0.385 mmol), HOBt (0.052 g, 0.38 mmol) and trimethylamine (0.15 mL, 1.05 mmol) in DMF (6 mL) was added a solution of HBTU (0.146 g, 0.44 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 48 hours. The reaction was quenched with water (1 mL) and the solvent was evaporated under reduced pressure. The residue was taken in CH₂Cl₂ (120 mL), washed with 5% aq. NaHCO₃ (1×80 mL) and brine (1×70 mL). The organic part was dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by preparative HPLC to give 56.

A solution of 56 in 4N HCl in dioxane (6 mL) was stirred at room temperature for 1.5 hours. Solvent was evaporated under pressure, the residue was co-evaporated with IPAc and dried to give the deprotected product 57 (0.052 g, 22% from 1) as an oil.

Alternative Procedure for 3-Val-Levorphanol 6

To a solution of levorphanol 1 (0.425 g, 1.65 mmol), Boc-Val-OH 2 (0.377 g, 1.73 mmol), HOBt (0.235 g, 1.73 mmol) and trimethylamine (0.57 mL, 4.1 mmol) in DMF (8 mL) was added a solution of HBTU (0.655 g, 1.73 mmol) in DMF (4 mL) at 0° C. After the addition, the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (1 mL) and the solvent was evaporated under reduced pressure. The residue was taken in EtOAc (125 mL), washed with 5% aq. NaHCO₃ (2×75 mL) and brine (1×75 mL). The organic part was dried over anhydrous Na₂SO₄ and evaporated to dryness. The solid residue was purified by preparative HPLC to give 3-(Boc-Val)-levorphanol 3.

3-(Boc-Val)-levorphanol 3 was dissolved in dioxane (3 mL) and to the solution was added 4 N HCl in dioxane (10 mL). The reaction mixture was stirred at room temperature for 2.5 hours. The solvent was evaporated under reduced pressure, the residue was co-evaporated with IPAc and dried to give the 3-Val-levorphanol 6 as a white solid (0.55 g, 77% yield from levorphanol).

Alternative Procedure for 3-Val-Levorphanol 6

A solution of levorphanol 1 (0.1 g, 0.39 mmol), 1,2,2,6,6-pentaethylpiperidine (0.15 mL, 1.25 mmol) and Boc-Val-O—CH₂—Cl (0.155 g, 0.58 mmol) in CH₃CN (8 mL) was heated at 75° C. for 12 hours. Solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC to give compound 3 (0.14 g, 78%) as white solid.

A solution of compound 3 in 4N HCl/dioxane (8 mL) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, the residue was co-evaporated with IPAc and dried to give compound 6 in quantitative yield.

Alternative Procedure for 3-Phe-Levorphanol 7

A solution of levorphanol 1 (0.077 g, 0.3 mmol), 1,2,2,6,6-pentaethylpiperidine (0.065 mL, 0.42 mmol) and Boc-Phe-O—CH₂—Cl (0.113 g, 0.36 mmol) in CH₃CN (8 mL) was heated at 65° C. for 7 hours. Solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC to give 4 as a white solid (0.105 g, 69%).

Compound 4 was dissolved in 4N HCl/dioxane (6 mL) and the solution was stirred at room temperature for 1 hour. Solvent was evaporated under reduced pressure and to the residue IPAc was added. The suspension was stirred for 15 minutes. The precipitate was filtered, washed with IPAc and dried to give compound 6 (0.09 g, 91%) as white solid.

3-(Acetyl-Val)-Levorphanol 58

A solution of 3-Val-levorphanol 6 (0.2 g, 0.47 mmol) and TEA (0.39 mL, 2.82 mmol) in CH₂Cl₂ (10 mL) was cooled to 0-5° C. and a solution of acetyl chloride (0.133 mL, 1.86 mmol) in CH₂Cl₂ (2 mL) was added drop-wise. After the addition of acetyl chloride, the reaction mixture was stirred at 0-5° C. for 1.5 hours. Solvents were evaporated under reduced pressure and the residue was purified by preparative HPLC to give 3-(acetyl-Val)-levorphanol.

To a solution of 3-(acetyl-Val)-levorphanol in dioxane (3 mL) was added 4 N HCl in dioxane (3 mL). The solution was stirred at room temperature for 10 minutes and then evaporated to dryness under reduced pressure. The residue was co-evaporated with IPAc and dried to give the hydrochloride salt 58 as white solid (0.175 g, 85% yield).

3-(Gly-Gly)-Levorphanol 63

To a solution of levorphanol 1 (0.193 g, 0.75 mmol), Boc-Gly-Gly-OH (0.191 g, 0.82 mmol), HOBt (0.101 g, 0.75 mmol) and trimethylamine (0.21 mL, 1.5 mmol) in DMF (8 mL) was added a solution of HBTU (0.313 g, 0.82 mmol) in DMF (4 mL). After the addition, the reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched with water (1 mL) and the solvent was evaporated under reduced pressure. The residue was taken in EtOAc (125 mL), washed with 5% aq. NaHCO₃ (2×75 mL) and brine (1×75 mL). The organic layer was dried over anhydrous Na₂SO₄ and evaporated to dryness. The solid residue was purified by preparative HPLC to give 3-(Boc-Gly-Gly)-levorphanol 60.

Compound 7 was dissolved in 4 N HCl in dioxane (8 mL) and the solution was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure, the residue was co-evaporated with IPAc and dried to give the 3-(Gly-Gly)-levorphanol 63 as a white solid (0.175 g, 52% yield from levorphanol).

3-(Val-Gly)-Levorphanol 64

3-(Val-Gly)-levorphanol was synthesized following the same method as described for compound 63 but using of levorphanol (0.193 g, 0.75 mmol) and Boc-Val-Gly-OH (0.227 g, 0.825 mmol). Yield of product 3-(Val-Gly)-levorphanol 64: 0.245 g (67% from levorphanol).

3-(Ala-Pro)-Levorphanol 65

3-(Ala-Pro)-levorphanol 65 was synthesized following the same method as described for compound 63 but using of levorphanol (0.193 g, 0.75 mmol) and Boc-Ala-Pro-OH (0.236 g, 0.825 mmol). Yield of product 3-(Ala-Pro)-levorphanol 65: 0.21 g (56% from levorphanol).

The presently described technology and its advantages will be better understood by reference to the following examples. These examples are provided to describe specific embodiments of the present technology. By providing these specific examples, it is not intended to limit the scope and spirit of the present technology. It will be understood by those skilled in the art that the full scope of the presently described technology encompasses the subject matter defined by the claims appending this specification, and any alterations, modifications, or equivalents of those claims.

EXAMPLES

For each of the examples below, exemplary conjugates of the present technology were synthesized as described above.

Example 1: Comparison of Oral PK Profiles of Conjugates of Levorphanol in Rats

Conjugate salts of levorphanol and levorphanol tartrate comparator compound were dissolved in an appropriate vehicle and administered in rats via oral gavage. A summary of the doses and vehicles used for each compound is provided in Table 1 below. Whole blood samples were collected via retro-orbital bleeding at 0.25, 0.5, 1, 2, 3, 4, and optionally at 6 hours postdose. Blood samples were centrifuged and the resulting plasma samples were collected for analysis of levorphanol concentrations by LC-MS/MS. PK profiles comparing the plasma concentrations of levorphanol released from the conjugates and from the levorphanol tartrate comparator are shown in FIGS. 13-22.

TABLE 1 Conju- Compar- gate ator^(a) Dose Dose Vehi- Conjugate (mg/kg) (mg/kg) cle^(b) ROA^(c) 3-Val-levorphanol 2 HCl 6.32 6.00 Water Oral 3-Phe-levorphanol 2 HCl 2.31 2.00 Water Oral 3-(PhePhePhe)-levorphanol 3.24 2.00 Water Oral 2 HCl 3-(ValValPhe)-levorphanol 3.05 2.00 Water Oral 2 HCl 3-(acetyl-Tyr)-levorphanol HCl 2.25 2.00 Water Oral 3-(acetyl-Val)-levorphanol HCl 2.14 2.00 50% Oral PEG/ water 3-(N-acetyl-Val-OCH₂OC(O))- 2.50 2.00 50% Oral levorphanol HCl PEG/ water 3-(N,O-diacetyl-Tyr- 2.77 2.00 Water Oral OCH₂OC(O))-levorphanol HCl 3-(GlyGly)-levorphanol 2 HCl 2.67 2.00 Water Oral 3-(ValGly)-levorphanol 2 HCl 2.86 2.00 Water Oral 3-(AlaPro)-levorphanol 2 HCl 2.91 2.00 Water Oral 3-(acetyl-OCH₂C(O))- 1.78 2.00 Water Oral levorphanol HCl 3-cinnamoyl-levorphanol HCl 1.91 2.00 Water Oral 3-(butanoyl-OCH₂OC(O))- 1.98 2.00 Water Oral levorphanol HCl 3-(H₂N-(PEG)₆-CH₂CH₂C(O))- 3.00 2.00 Water Oral levorphanol 2 HCl ^(a)comparator = levorphanol tartrate; the comparator and conjugate doses are equimolar ^(b)the same vehicle was used for conjugate and comparator ^(b)ROA = route of administration

Example 2: Comparison of Intranasal PK Profiles of Conjugates of Levorphanol in Rats

Conjugate salts of levorphanol and levorphanol tartrate comparator compound were dissolved in an appropriate vehicle and administered in rats by slowly adding the respective dosing solution drop-wise and alternating into the nasal openings. A summary of the doses and vehicles used for each compound is provided in Table 2 below. Whole blood samples were collected via retro-orbital bleeding at 5 minutes and at 0.25, 0.5, and 1 hours postdose. Blood samples were centrifuged and the resulting plasma samples were collected for analysis of levorphanol concentrations by LC-MS/MS. PK profiles comparing the plasma concentrations of levorphanol released from the conjugates and from the levorphanol tartrate comparator are shown in FIGS. 23-26.

TABLE 2 3-(ValValPhe)-levorphanol 0.31 0.20 Water Intranasal 2 HCl 3-(acetyl-Tyr)-levorphanol HCl 0.23 0.20 Water Intranasal 3-Val-levorphanol 2 HCl 0.19 0.20 Water Intranasal 3-(acetyl-Ile)-levorphanol HCl 0.20 0.20 Water Intranasal ^(a) comparator = levorphanol tartrate; the comparator and conjugate doses are equimolar ^(b) the same vehicle was used for conjugate and comparator ^(b) ROA = route of administration

Example 3: Comparison of Intravenous PK Profiles of Conjugates of Levorphanol in Rats

3-Val-levorphanol hydrochloride conjugate and levorphanol tartrate comparator compound were dissolved in an appropriate vehicle and administered in rats by injecting the solution into the tail vein. A summary of the dose and vehicle used for each compound is provided in Table 3 below. Whole blood samples were collected via retro-orbital bleeding at 5 minutes and at 0.25, 0.5, 1 and 2 hours postdose. Blood samples were centrifuged and the resulting plasma samples were collected for analysis of levorphanol concentrations by LC-MS/MS. PK profiles comparing the plasma concentrations of levorphanol released from the conjugate and from the levorphanol tartrate comparator are shown in FIG. 27.

TABLE 3 3-Val-levorphanol 2 HCl 0.194 0.20 PBS Intravenous ^(a) comparator = levorphanol tartrate; the comparator and conjugate doses are equimolar ^(b) the same vehicle was used for conjugate and comparator ^(b) ROA = route of administration

In the present specification, use of the singular includes the plural except where specifically indicated.

The compounds, compositions, and methods described herein can be illustrated by the following embodiments enumerated in the numbered paragraphs that follow:

1. A compound or composition comprising at least one conjugate of levorphanol having the following general formula:

-   -   where L is absent, or is

-   -   Y is absent, or [A-X—Z]_(n)     -   where A, X, Z are independently absent or selected from —O—, —S—         or —(CR¹R²)_(k)—     -   R¹, R² are each independently selected from H, alkyl, aryl,         alkyl aryl, alkoxy, haloalkyl, haloaryl     -   n and k are independently 1-4     -   G_(m) is absent or selected independently for each repeating         subunit from H, oxoacid, polyethylene glycol having from 2 to 5         ethylene oxide units, or a vitamin compound, and m is 1-4,         except m is 1 when G is H;     -   or a pharmaceutically acceptable salt thereof.

2. The compound or composition of paragraph 1, wherein L and Y are absent, G is at least one oxoacid and m is 1-3.

3. The compound or composition of paragraph 1, wherein L is present, A and Z are —O— and X is —(CR¹R²)_(k)—, G is at least one oxoacid and m is 1-3.

4. The compound or composition of paragraph 2 or 3, wherein the at least one oxoacid is at least one carboxylic acid.

5. The compound or composition of paragraph 2 or 3, wherein the at least one oxoacid is at least one amino acid.

6. The compound or composition of paragraph 2 or 3, wherein the at least one oxoacid is a combination of at least one carboxylic acid and at least one amino acid.

7. The compound or composition of paragraph 4 or paragraph 6, wherein the carboxylic acid is selected from the group consisting of aliphatic carboxylic acid, aryl carboxylic acid, dicarboxylic acid, and polycarboxylic acid.

8. The compound or composition of paragraph 7, wherein the carboxylic acid is an aliphatic carboxylic acid selected from the group consisting of saturated carboxylic acids, monounsaturated carboxylic acids, polyunsaturated carboxylic acids, acetylenic carboxylic acids, substituted carboxylic acids, heteroatom containing carboxylic acids and ring containing carboxylic acids.

9. The compound or composition of paragraph 8, wherein the saturated carboxylic acid is selected from the group consisting of methanoic, ethanoic, propanoic, butanoic, pentanoic, hexanoic, heptanoic, octanoic, 2-propylpentanoic acid, pivalic acid, nonanoic, decanoic, dodecanoic, tetradecanoic, hexadecanoic, heptadecanoic, octadecanoic, and eicosanoic acid.

10. The compound or composition of paragraph 8, wherein the monounsaturated carboxylic acid is selected from the group consisting of 4-decenoic, 9-decenoic, 5-lauroleic, 4-dodecenoic, 9-tetradecenoic, 5-tetradecenoic, 4-tetradecenoic, 9-hexadecenoic, 6-hexadecenoic, 6-octadecenoic, and 9-octadecenoic acid.

11. The compound or composition of paragraph 8, wherein the polyunsaturated carboxylic acid is selected from the group consisting of sorbic, octadecadienoic, octadecatrienoic, octadecatetraenoic, eicosatrienoic, eicosatetraenoic, eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids.

12. The compound or composition of paragraph 8, wherein the acetylenic carboxylic acid is selected from the group consisting of octadecynoic, octadecenynoic, 6,9-octadecenynoic, heptadecenynoic, tridecatetraenediynoic, tridecadienetriynoic, octadecadienediynoic, heptadecadienediynoic, octadecadienediynoic, octadecenediynoic, and octadecenetriynoic acids.

13. The compound or composition of paragraph 8, wherein the substituted carboxylic acid is selected from the group consisting of methylpropanoic, isovaleric, methylhexadecanoic, 8-methyl-6-nonenoic, methyloctadecanoic, trimethyloctacosanoic, trimethyltetracosenoic, heptamethyltriacontanoic, tetramethylhexadecanoic, tetramethylpentadecanoic, lactic, glyceric, glycolic, threonic, 3-hydroxypropionic, hydroxyoctadecatrienoic, hydroxyoctadecenoic, hydroxytetracosanoic, 2-hydroxybutyric, 3-hydroxybutyric, 4-hydroxybutyric, 4-hydroxypentanoic, hydroxyoctadecadienediynoic, hydroxyoctadecadienoic, 10-hydroxydecanoic, hydroxydecenoic, hydroxyeicosenoic, hydroxyeicosadienoic, hydroxyhexadecanoic, dihydroxytetracosenoic, dihydroxydocosanoic, hydroxydocosanoic, trihydroxyoctadecanoic, trihydroxyhexadecanoic, trihydroxyicosahexaenoic, trihydroxyicosapentaenoic, 2-methoxy-5-hexadecenoic, 2-methoxy hexadecanoic, 7-methoxy-4-tetradecenoic, 9-methoxypentadecanoic, 11-methoxyheptadecanoic, 3-methoxydocosanoic, diacetoxydocosanoic, 2-acetoxydocosanoic, 2-acetoxytetracosanoic, 2-acetoxyhexacosanoic, 9-oxononanoic, oxodecanoic, oxododecenoic, hydroxyoxodecenoic, 10-oxo-8-decenoic, fluorooctadecenoic, fluorodecanoic, fluorotetradecanoic, fluorohexadecanoic, fluorooctadecadienoic, chlorohydroxyhexadecanoic, chlorohydroxyoctadecanoic, dichlorooctadecanoic, 3-bromo-2-nonaenoic, 9,10-dibromooctadecanoic, 9,10,12,13-tetrabromooctadecanoic, 10-nitro-9,12-octadecadienoic, 12-nitro-9,12-octadecadienoic, 9-nitro-9-octadecenoic, 9-oxo-2-decenoic, 9-oxo-13-octadecenoic, oxooctadecatrienoic, 15-oxo-18-tetracosenoic, 17-oxo-20-hexacosenoic, and 19-oxo-22-octacosenoic acids.

14. The compound or composition of paragraph 8, wherein the heteroatom containing carboxylic acid is selected from the group consisting of 9-(1,3-nonadienoxy)-8-nonenoic, 9-(1,3,6-nonatrienoxy)-8-nonenoic, 12-(1-hexenoxy)-9,11-dodecadienoic, 12-(1,3-hexadienoxy)-9,11-dodecadienoic, 2-dodecylsulfanylacetic, 2-tetradecylsulfanylacetic, 3-tetradecylsulfanylprop-2-enoic, and 3-tetradecylsulfanylpropanoic acid.

15. The compound or composition of paragraph 8, wherein the ring containing carboxylic acid is selected from the group consisting of 10-(2-Hexylcyclopropyl)decanoic, 3-(2-[6-bromo-3,5-nondienylcyclopropyl)propanoic, 9-(2-hexadecylcyclopropylidene)non-5-enoic, 8-(2-octyl-1-cyclopropenyl)octanoic, 7-(2-octyl-1-cyclopropenypeptanoic, 9,10-epoxyoctadecanoic, 9,10-epoxyl2-octadecenoic, 12,13-epoxy-9-octadecenoic, 14,15-epoxy-11-eicosenoic, 11-(2-cyclopenten-1-yl)undecanoic, 13-(2-cyclopenten-1-yl)tridecanoic, 13-(2-cyclopentenyl)-6-tridecenoic, 11-cyclohexylundecanoic, 13-cyclohexyltridecanoic, 7-(3,4-dimethyl-5-pentylfuran-2-yl)heptanoic, 9-(4-methyl-5-pentylfuran-2-yl)nonanoic, 4-[5]-ladderane-butanoic, 6-[5]-ladderane-hexanoic, and 6-[3]-ladderane-hexanoic acid.

16. The compound or composition of paragraph 7, wherein the carboxylic acid is a benzoate or a heteroaryl carboxylic acid.

17. The compound or composition of paragraph 16, wherein the benzoate is selected from the group consisting of benzoic acid, hydroxybenzoate, and combinations thereof.

18. The compound or composition of paragraph 17, wherein the hydroxybenzoate is selected from the group consisting of salicylic acid, acetylsalicylic acid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids, 4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflunisal, o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylic acid, protocatechuic acid, gentisic acid, piperonylic acid, 3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylic acid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid, 4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid, vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid, 2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid, 2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid (3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid, 2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA), 4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringic acid, and 3,4,5-trimethoxybenzoic acid.

19. The compound or composition of paragraph 16, wherein the heteroaryl carboxylic acid is selected from the group consisting of nicotinic acid, isonicotinic acid, picolinic acid, 3-hydroxypicolinic acid, 6-hydroxynicotinic acid, citrazinic acid, 2,6-dihydroxynicotinic acid, kynurenic acid, xanthurenic acid, 6-hydroxykynurenic acid, 8-methoxykynurenic acid, 7,8-dihydroxykynurenic acid, and 7,8-dihydro-7,8-dihydroxykynurenic acid.

20. The compound or composition of paragraph 4 or 6, wherein the carboxylic acid is a phenylacetate, a branched phenylpropionate, an unbranched phenylpropionate (benzylacetate), a phenylpropenoate (cinnamate), salts thereof, derivatives thereof, or a combination thereof.

21. The compound or composition of paragraph 20, wherein the phenylacetate is selected from the group consisting of phenylacetic acid (hydratropic acid), 2-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid, homoprotocatechuic acid, homogentisic acid, 2,6-dihydroxyphenylacetic acid, homovanillic acid, homoisovanillic acid, homoveratric acid, atropic acid, d,l-tropic acid, diclofenac, d,l-mandelic acid, 3,4-dihydroxy-d,l-mandelic acid, vanillyl-d,l-mandelic acid, isovanillyl-d,l-mandelic acid, ibuprofen, fenoprofen, carprofen, flurbiprofen, ketoprofen, and naproxen.

22. The compound or composition of paragraph 20, wherein the carboxylic acid is a benzylacetate selected from the group consisting of benzylacetic acid, melilotic acid, 3-hydroxyphenylpropanoic acid, 4-hydroxyphenylpropanoic acid, 2,3-dihydroxyphenylpropanoic acid, d,l-phenyllactic acid, o,m,p-hydroxy-d,l-phenyllactic acid, and phenylpyruvic acid.

23. The compound or composition of paragraph 20, wherein the carboxylic acid is a cinnamate, derivatives thereof, or combinations thereof.

24. The compound or composition of paragraph 23, wherein the cinnamate is selected from the group consisting of cinnamic acid, o,m,p-coumaric acid, 2,3-dihydroxycinnamic acid, 2,6-dihydroxycinnamic acid, caffeic acid, ferulic acid, isoferulic acid, 5-hydroxyferulic acid, sinapic acid, and 2-hydroxy-3-phenylpropenoic acid.

25. The compound or composition of paragraph 7, wherein the dicarboxylic acid is of the general formula HOOC—R—COOH, where R is selected from the group consisting of an alkyl, alkenyl, alkynyl, aryl group, and derivatives thereof.

26. The compound or composition of paragraph 25, wherein the dicarboxylic acid is selected from the group consisting of oxalic, malonic, succinic, glutaric, adipic, pimelic, suberic, azelaic, sebacic, brassylic, thapsic, malic, tartaric, dihydroxymesoxalic, α-hydroxyglutaric, methylmalonic, meglutol, diaminopimelic, carbamoyl aspartic, fumaric, maleic, mesaconic, 3-methylglutaconic, traumatic, phthalic acid, isophthalic, terephthalic, and dipicolinic acid.

27. The compound or composition of paragraph 7, wherein the polycarboxylic acid is selected from the group consisting of citric acid, isocitric, carballylic, and trimesic acid.

28. The compound or composition of paragraph 5 or 6, wherein the amino acid is selected from standard amino acids, non-standard amine acids, synthetic amino acids, and combinations thereof.

29. The compound or composition of paragraph 28, wherein the amino acid is a standard amino acid.

30. The compound or composition of paragraph 28, wherein the amino acid is a non-standard amino acid.

31. The compound or composition of paragraph 28, wherein the amino acid is a synthetic amino acid.

32. The compound or composition of paragraph 1, wherein L is present, A is —CR¹R²—, X is absent, Z is —CR¹R²— or absent, and G is polyethylene glycol.

33. The compound or composition of paragraph 32, wherein the terminal hydroxyl group of the polyethylene glycol is substituted with an amino, azide, or methoxy group.

34. The compound or composition of paragraph 32 or 33, wherein R¹ and R² are H.

35. The compound or composition of paragraph 1, wherein L is present, A is —O—, X and Z are —(CR¹R²)_(k)—, G is H and m is 1.

36. The compound or composition of paragraph 35, wherein R¹ and R² are H and k is 1 to 4.

37. The compound or composition of paragraph 1, wherein L is present, A is —(CR¹R²)_(k)—, X and Z are absent, G is acetic acid and m is 1.

38. The compound or composition of paragraph 37, wherein R¹ is H and R² is either H, alkyl or aryl, and k is 1 to 4.

39. The compound or composition of paragraph 1, wherein L and Y are absent and G is a vitamin compound.

40. The compound or composition of paragraph 1, wherein L is present, A is —O—, X and Z are absent, and G is a vitamin compound.

41. The compound or composition of paragraph 1, wherein L is present, Y is absent, m is 2 and G_(m) can be represented as G¹ and G² where G¹ is a hydroxycarboxylic acid, and G² is a vitamin compound.

42. The compound or composition of paragraph 1, wherein L and Y are absent, m is 2 and G_(m) can be represented as G¹ and G² where G¹ is a dicarboxylic acid, and G² is a vitamin compound.

43. The compound or composition of paragraph 39, wherein the vitamin compound is a water soluble vitamin compound selected from biotin, folic acid, niacin, and pantothenic acid.

44. The compound or composition of paragraph 40, wherein the vitamin compound is a water soluble vitamin compound selected from ascorbic acid, riboflavin, thiamin, pantothenic acid, pyridoxine, pyridoxamine, and pyridoxal.

45. The compound or composition of paragraph 40, wherein the vitamin compound is a fat soluble vitamin compound selected from retinol, cholecalciferol, ergocalciferol, and tocopherols.

46. The compound or composition of paragraph 41 or 42, wherein G² is a water soluble vitamin compound selected from ascorbic acid, riboflavin, thiamin, pantothenic acid, pyridoxine, pyridoxamine, and pyridoxal.

47. The compound or composition of paragraph 41 or 42, wherein G² is a fat soluble vitamin compound selected from retinol, cholecalciferol, ergocalciferol, and tocopherols.

48. The compound or composition of any one of paragraphs 1-47, wherein the pharmaceutically acceptable salt of the conjugate is a pharmaceutically acceptable anionic salt form or salt mixtures thereof.

49. The compound or composition of paragraph 48, wherein the anionic salt form is selected from the group consisting of acetate, l-aspartate, besylate, bicarbonate, carbonate, d-camsylate, l-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, d-lactate, l-lactate, d,l-lactate, d,l-malate, l-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, d-tartrate, l-tartrate, d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, or undecylenate.

50. The compound or composition of any one of paragraphs 1-47, wherein the conjugate is a neutral conjugate.

51. The compound or composition of any one of paragraphs 1-47, wherein the conjugate is a free acid.

52. The compound or composition of any one of paragraphs 1-47, wherein the conjugate is a free base.

53. The compound or composition of any one of paragraphs 1-52, wherein the at least one conjugate is in a mixture of racemates, wherein the racemate comprises racemorphan.

54. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-Val-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

55. The compound or composition of paragraph 1 wherein the at least one conjugate of levorphanol comprises 3-(PhePhePhe)-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

56. The compound or composition of paragraph 1 wherein the at least one conjugate of levorphanol comprises 3-(ValValPhe)-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

57. The compound or composition of paragraph 1 wherein the at least one conjugate of levorphanol comprises 3-(AlaAlaVal)-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

58. The compound or composition of paragraph 1 wherein the at least one conjugate of levorphanol comprises 3-(GlyGlyAla)-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

59. The compound or composition of paragraph 1 wherein the at least one conjugate of levorphanol comprises 3-hippuryl-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

60. The compound or composition of paragraph 1 wherein the at least one conjugate of levorphanol comprises 3-(N,O-diacetyl-Tyr)-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

61. The compound or composition of paragraph 1 wherein the at least one conjugate of levorphanol comprises 3-(N-acetyl-Ile)-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

62. The compound or composition of paragraph 1 wherein the at least one conjugate of levorphanol comprises 3-(ProProPhe)-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

63. The compound or composition of paragraph 1 wherein the at least one conjugate of levorphanol comprises 3-(GlyGly)-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

64. The compound or composition of paragraph 1 wherein the at least one conjugate of levorphanol comprises 3-(ValGly)-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

65. The compound or composition of paragraph 1 wherein the at least one conjugate of levorphanol comprises 3-(AlaPro)-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

66. The compound or composition of paragraph 1 wherein the at least one conjugate of levorphanol comprises 3-cinnamoyl-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

67. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-biotinyl-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

68. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(N,O-diacetyl-Tyr-OCH₂OC(O))-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

69. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(N-acetyl-Val-OCH₂OC(O))-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

70. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(cinnamoyl-OCH₂OC(O))-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

71. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(benzoyl-OCH₂OC(O))-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

72. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(butanoyl-OCH₂OC(O))-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

73. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(N,O-diacetyl-Lys-OCH₂OC(O))-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

74. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(acetyl-OCH(CH₃)C(O))-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

75. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(acetyl-OCH(phenyl)C(O))-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

76. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(methoxy-PEG₂-CH₂C(O))-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

77. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(methoxy-(ethoxy)-CH₂C(O))-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

78. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(succinoyl-Val)-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

79. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(H₂N-PEG₂-CH₂C(O))-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

80. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(N₃-(PEG)₄-CH₂CH₂C(O))-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

81. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(H₂N-(PEG)₆-CH₂CH₂C(O))-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

82. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(propyl-SC(O))-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

83. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(acetyl-Val)-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

84. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-(N-acetyl-Tyr)-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

85. The compound or composition of paragraph 1, wherein the at least one conjugate of levorphanol comprises 3-Phe-levorphanol having the following structural formula, or a pharmaceutically acceptable salt thereof:

86. The composition of any one of paragraphs 1-85, wherein the at least one conjugate is present in an amount of about 0.5 mg or higher, about 2.5 mg or higher, about 5 mg or higher, about 10 mg or higher, about 20 mg or higher, about 50 mg or higher, or about 100 mg or higher.

87. The composition of any one of paragraphs 1-86, wherein the at least one conjugate is provided in a dosage form selected from the group consisting of: a tablet, a capsule, a caplet, a suppository, a troche, a lozenge, an oral powder, a solution, an oral film, a thin strip, a slurry, and a suspension.

88. The composition of any one of paragraphs 1-87, wherein the at least one conjugate exhibits a slower rate of release over time as compared to unmodified levorphanol.

89. The composition of any one of paragraphs 1-88, wherein the composition further comprises one or more excipients.

90. The composition of paragraph 89, wherein the one or more excipients is at least one filler, at least one glidant, at least one binder, at least one diluent, at least one lubricant, at least one surfactant, at least one plasticizer, at least one disintegrant, or a combination thereof.

91. The composition of any one of paragraphs 1-90, wherein the composition further comprises at least one additional active pharmaceutical ingredient.

92. The composition of paragraph 91, wherein the additional active pharmaceutical ingredient is hydromorphone, hydrocodone, oxycodone, oxymorphone, conjugates thereof, or combinations thereof.

93. The composition of paragraph 91, wherein the additional active pharmaceutical ingredient is in the form of a second conjugate.

94. The composition of paragraph 93, wherein the second conjugate is a levorphanol conjugate that is different from the at least one conjugate.

95. The composition of paragraph 93, wherein the second conjugate is a dextrorphan conjugate.

96. A method of treating a patient having pain, comprising orally administering to the patient a pharmaceutically effective amount of a composition comprising at least one conjugate of levorphanol and at least one oxoacid, polyethylene glycol, vitamin compound, or a combination thereof.

97. The method of paragraph 96, wherein the patient is a pediatric patient.

98. The method of paragraph 96, wherein the patient is an elderly patient.

99. The method of paragraph 96, wherein the patient is a normative patient.

100. The method of paragraph 96, wherein the patient is a neonatal patient.

101. The method of paragraph 96, wherein the patient is an adolescent patient.

102. A method of using opioid rotation to treat pain in a patient who is determined to be refractory or non-responsive to a first opioid active pharmaceutical ingredient, the method comprising administering to the patient a second active pharmaceutical ingredient, wherein the second active pharmaceutical ingredient is at least one conjugate of levorphanol and at least one oxoacid, polyethylene glycol, vitamin compound, or a combination thereof.

103. The method of claim 102, wherein the first opioid active pharmaceutical ingredient is selected from the group consisting of hydromorphone, hydrocodone, oxycodone, oxymorphone, conjugates thereof, and combinations thereof.

104. A pharmaceutical kit comprising:

-   -   a specified amount of individual doses in a package, wherein         each dose comprises a pharmaceutically effective amount of at         least one conjugate of levorphanol and at least one oxoacid,         polyethylene glycol, vitamin compound, or a combination thereof.

105. The pharmaceutical kit of paragraph 104, wherein the kit further comprises:

-   -   instructions for use of the kit in a method for treating pain in         a human or animal patient.

106. A compound having the following structural formula:

107. A compound having the following structural formula:

108. A compound having the following structural formula:

109. A compound having the following structural formula:

110. A compound having the following structural formula:

111. A compound having the following structural formula:

112. A compound having the following structural formula:

113. A compound having the following structural formula:

114. A compound having the following structural formula:

115. A compound having the following structural formula:

116. A compound having the following structural formula:

117. A compound having the following structural formula:

118. A compound having the following structural formula:

119. A compound having the following structural formula:

120. A compound having the following structural formula:

121. A compound having the following structural formula:

122. A compound having the following structural formula:

123. A compound having the following structural formula:

124. A compound having the following structural formula:

125. A compound having the following structural formula:

126. A compound having the following structural formula:

127. A compound having the following structural formula:

128. A compound having the following structural formula:

129. A compound having the following structural formula:

130. A compound having the following structural formula:

131. A compound having the following structural formula:

132. A compound having the following structural formula:

133. A compound having the following structural formula:

134. A compound having the following structural formula:

135. A compound having the following structural formula:

136. A compound having the following structural formula:

137. A compound having the following structural formula:

The presently described technology is now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to practice the same. It is to be understood that the foregoing describes preferred embodiments of the technology and that modifications may be made therein without departing from the spirit or scope of the invention as set forth in the appended claims. 

1-115. (canceled)
 116. A compound having the following general formula:

where L is absent, or is

Y is absent, or [A-X—Z]_(n) where A, X, Z are independently absent or selected from —O—, —S— or —(CR¹R²)_(k)— R¹, R² are each independently selected from H, alkyl, aryl, alkylaryl, alkoxy, haloalkyl, haloaryl n and k are independently 1-4 G_(m) is absent or selected independently for each repeating subunit from H, oxoacid, polyethylene glycol having from 2 to 5 ethylene oxide units, or a vitamin compound, and m is 1-4, except m is 1 when G is H; or a pharmaceutically acceptable salt thereof.
 117. The compound of claim 116, wherein the oxoacid is at least one carboxylic acid, is at least one amino acid, or combination of at least one carboxylic acid and at least one amino acid.
 118. The compound of claim 117, wherein the at least one carboxylic acid is selected from the group consisting of aliphatic carboxylic acid, saturated carboxylic acids, monounsaturated carboxylic acids, polyunsaturated carboxylic acids, acetylenic carboxylic acids, substituted carboxylic acids, heteroatom containing carboxylic acids, ring containing carboxylic acids, aryl carboxylic acid, dicarboxylic acid, benzoate, heteroaryl carboxylic acid, polycarboxylic acid, phenylacetate, a branched phenylpropionate, an unbranched phenylpropionate (benzylacetate), a phenylpropenoate (cinnamate), salts thereof, derivatives thereof, and combinations thereof.
 119. The compound of claim 118, wherein the saturated carboxylic acid is selected from the group consisting of methanoic, ethanoic, propanoic, butanoic, pentanoic, hexanoic, heptanoic, octanoic, 2-propylpentanoic acid, pivalic acid, nonanoic, decanoic, dodecanoic, tetradecanoic, hexadecanoic, heptadecanoic, octadecanoic, and eicosanoic acid.
 120. The compound of claim 118, wherein the benzoate is selected from the group consisting of benzoic acid, hydroxybenzoate, and combinations thereof.
 121. The compound of claim 118, wherein the phenylacetate is selected from the group consisting of phenylacetic acid (hydratropic acid), 2-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid, homoprotocatechuic acid, homogentisic acid, 2,6-dihydroxyphenylacetic acid, homovanillic acid, homoisovanillic acid, homoveratric acid, atropic acid, d,l-tropic acid, diclofenac, d,l-mandelic acid, 3,4-dihydroxy-d,l-mandelic acid, vanillyl-d,l-mandelic acid, isovanillyl-d,l-mandelic acid, ibuprofen, fenoprofen, carprofen, flurbiprofen, ketoprofen, and naproxen.
 121. The compound of claim 118, wherein the cinnamate is selected from the group consisting of cinnamic acid, o,m,p-coumaric acid, 2,3-dihydroxycinnamic acid, 2,6-dihydroxycinnamic acid, caffeic acid, ferulic acid, isoferulic acid, 5-hydroxyferulic acid, sinapic acid, and 2-hydroxy-3-phenylpropenoic acid.
 123. The compound of claim 118, wherein the dicarboxylic acid is of the general formula HOOC—R—COOH, where R is selected from the group consisting of an alkyl, alkenyl, alkynyl, arylgroup, and derivatives thereof, or selected from the group consisting of oxalic, malonic, succinic, glutaric, adipic, pimelic, suberic, azelaic, sebacic, brassylic, thapsic, malic, tartaric, dihydroxymesoxalic, α-hydroxyglutaric, methylmalonic, meglutol, diaminopimelic, carbamoyl aspartic, fumaric, maleic, mesaconic, 3-methylglutaconic, traumatic, phthalic acid, isophthalic, terephthalic, and dipicolinic acid.
 124. The compound of claim 117, wherein the at least one amino acid is selected from standard amino acids, non-standard amine acids, synthetic amino acids, and combinations thereof.
 125. The compound of claim 116, wherein L and Y are absent, G is at least one oxoacid and m is 1-3.
 126. The compound of claim 116, wherein L is present, A and Z are —O— and X is —(CR¹R²)_(k)—, G is at least one oxoacid and m is 1-3.
 127. The compound of claim 116, wherein L is present, A is —CR¹R²—, X is absent, Z is —CR¹R²— or absent, and G is polyethylene glycol.
 128. The compound of claim 127, wherein the terminal hydroxyl group of the polyethylene glycol is substituted—with an amino, azide, or methoxy group.
 129. The compound of claim 127, wherein R¹ and R² are H.
 130. The compound of claim 116, wherein the compound has a structural formula selected from the group consisting of

and a pharmaceutically acceptable salt of the compound.
 131. A composition comprising a compound of claim 116, a pharmaceutically acceptable salt of the compound, or a combination thereof.
 132. The composition of claim 131, wherein the pharmaceutically acceptable salt is selected from the group consisting of acetate, l-aspartate, besylate, bicarbonate, carbonate, d-camsylate, l-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, d-lactate, l-lactate, d,l-lactate, d,l-malate, l-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, d-tartrate, l-tartrate, d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, or undecylenate.
 133. The composition of claim 131, wherein the compound is present in an amount of about 0.5 mg or higher.
 134. The composition of claim 131, wherein the compound is provided in a dosage form selected from the group consisting of a tablet, a capsule, a caplet, a suppository, a troche, a lozenge, an oral powder, a solution, an oral film, a thin strip, a slurry, and a suspension. 